PH26180A - A method for the preparation of 0-(2,2-di(C1C4alkoxy)ethylamino)-beta-cyanostyrene PR beta-nitrostyrene - Google Patents

Description

. : ' { 30,655-01 - 1 -

ARYLPYRROLE INSECTICIDAL

ACARICIDAL AND NEMATICIDAL AGENTS

AND METHODS FOR THE PREPARATION THEREOF Lo / if. te or Chere Loe + of J Fr {: an Loe. { or a . . Plo ' ’ | a / Cfo fod © Chl fe !

The present invention {is directed to certain novel arylpyrrole compounds that are highly effective insecticidal, acaricidal and nematicidal agents useful for the control of insect, acarid and nematode pests and for protecting agronomic crops, both growing and harvested, against the ravages of said pests. The present invention is also directed to methods for preparing the arylpyrrole compounds.

The novel arylpyrrole compounds of the present invention have the structural formula illus- trated as formula I:

L

W

H

} X v R

N

A wherein X is F, Cl, Br, I, or CF; y is F, Cl, Br, I,

CF, or CN; W 1s CN or NO, and A is H: C,17Cy alkyl optionally substituted with from one to three halogen atoms, one hydroxy, one C,-C, alkoxy or one C.-C, alkylthio, one phenyl optionally substituted with C1 Cy

2c 26180 alkyl or C,7C5 alkoxy or with one to three halogen atoms, one phenoxy optionally substituted with one to three halogen atoms or one benzyloxy optionally substituted with one halogen substituent: C=C, carbalkoxymethyl; C;-Cy alkenyl optionally substituted with from one to three halogen atoms; cyano; C,-C, alkynyl optionally substituted with one halogen atom; di-(c,-¢, alkyl) aminocarbonyl; or C,~Cq cycloalkylami- nocarbonyl; L is H, F, Cl or Br; and M and R are each independently H, C,-C, alkyl, C,-C4 alkoxy, C,7C5 alkylthio, C, C4 alkylsulfinyl, C.-C alkylsulfonyl, cyano, F, C1, Br, I, nitro, CF,, R,CF,Z, R,CO or NR,R,, and when M and R are on adjacent positions and taken with the carbon atoms to which they are attached they may form a ring in which MR represents the structure: 2 -0CH,0-, -0CF,0- or : ~

Z is S(O)n or 0; Ry is H, F, CHF, , CHFC1l, or CF,i R, is c,-C, alkyl, C,-C, alkoxy, or NR;R,: R, is H or C,-C, alkyl: R, is H, C,-Cy alkyl, or RCO; Rg is H or C.-C, alkyl: and n is an integer of 0, 1 or 2.

The term C4 Ce cycloalkylamino carbonyl means a C4 to Ce cycloalkylamino group attached directly to the carbonyl group through the nitrogen atom.

A preferred group of novel arylpyrroles of ’ the present invention are illustrated by formula II:

H

SE L

’ h n an

R wherein A, L, M, R, W, X and Y are as described above.

Another preferred group of novel arylpyrroles " of this invention are represented by formula III:

X

H L

7 \ H y N o (In wherein A, L, M, R, W, X and Y are as described above.

Another group of preferred arylpyrroles of the invention are depicted by formula IV:

L

Y X

L IM

N (IV)

A R wherein A, L, M, R, W, X and Y are as described above.

Yet another group of preferred arylpyrroles of this invention are delineated by formula V:

L

M

W

7 \ R (VD

Y N X

A wherein A, L, MR, W, X and Y are as described above;

7 : ECAC

DE 26180 ~ and still other preferred arylpyrroles of the invention * are depicted by formulas VI and VII:

X LM L

X osGn HEX u

YON yu R Rv N

A

VI) (VII) wherein A, L, M, R, W, X and Y are as described above.

Preferred formula I arylpyrroles of the invention are those in which A is hydrogen or C,-C4 alkoxymethyl; W is CN or NO, ; L is hydrogen or F; X and

Y are each Cl, Br or CF,i M is H, F, Cl or Br; and R is

F, Cl, Br, CF, or OCF, .

Preferred formula II compounds which are . especially effective as insecticidal, acaricidal and/or nematicidal agents are those in which A is hydrogen or

C.-C, alkoxymethyl; L is hydrogen; M is hydrogen, F, Cl or Br; R is F, Cl, Br, CF, or OCF, i W is CN and X and Y are each independently Cl, Br or CF,. other formula II compounds that are highly ’ effective as insecticidal, acaricidal and/or nema- ticidal agents are those in which A is hydrogen or

C,-C4 alkoxymethyl; L is hydrogen; M is hydrogen, F, Cl or Br; R is F, Cl, Br, CF, or OCF; W is NO, and X and y are each independently Cl, Br or CF,.

Illustrative of some of the insecticidal, acaricidal and nematicidal arylpyrroles of the present invention are: 4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole=3-carbo= nitrile; 4 5-dichloro-2-[p- (trifluoromethoxy)phenyljpyrrole=3- carbonitrile;

4-bromo-5-chloro-2-(p~chlorophenyl)pyrrole-3-carbo- nitrile; 5-bromo-4-chloro-2-(3,4~dichlorophenyl)pyrrole-3-carbo- nitrile;

4,5-dichloro-2-(o-chlorophenyl)pyrrole-3-carbonitrile; 2-(p-bromophenyl) -4,5-dichloropyrrole-3-carbonitrile; 4,5-dichloro-2-(a,a,a~trifluoro-p~tolyl)pyrrole-3-

carbonitrile; 4,5-dibromo-2-(a,a,a~trifluoro-p-tolyl)pyrrole-3-carbo-

nitrile; 4,5-dibromo-2-(o-chlorophenyl)pyrrole-3-carbonitrile; 4,5-dibromo-2-(p-chlorophenyl)pyrrole-3-carbonitrile; 4,5-dichloro-2-(2,4-dichlorophenyl)pyrrole-3-carbo-

nitrile;

4,5-dibromo-2-(2,4~dichlorophenyl)pyrrole-3-carbo-

nitrile; 2,3-dibromo-4-nitro-5-phenylpyrrole; 2-(p-bromophenyl)-4,5-dichloro-3-nitropyrrole; 2,3-dichloro-4-nitro-5-(e,a,a-trifluoro-p-tolyl) -

pyrrole; 4,5-dichloro-2-(m-chlorophenyl)pyrrole-3-carbonitrile; 4,5-dichloro-2-(p-chlorophenyl)pyrrole-3-carbonitrile;

. 4,5-dichloro-2-phenylpyrrole-3-carbonitrile; 2,3-dichloro-5-(p-chlorophenyl)-4-nitropyrrole:

2-bromo-3-chloro-5-(p~chlorophenyl)-4-nitropyrrole; 2,3-dibromo-5-(p-chlorophenyl-4-nitropyrrole; - 2,3-dichloro-4-nitro-5-phenylpyrrole; 3-bromo-2-chloro-4-nitro-5-(a,a,a-trifluoro-p-tolyl)-

pyrrole;

5-Chloro-2-(3,4-dichlorophenyl) -1-(methoxymethyl)-4-

(trifluoromethyl) pyrrole-3-carbonitrile; 5-Bromo-2-(m-fluorophenyl)-3-nitro-4- (trifluoromethyl) pyrrole; 2-(p-chlorophenyl)-5- (trifluoromethyl) pyrrole-3-carbo- nitrile;

6¥42H -6 - yoo 2010 3-Bromo-5- (m-fluorophenyl)-4-nitro-2~ (trifluoromethyl) : pyrrole; 4-Bromo-2-(p-chlorophenyl)-1-(ethoxymethyl)-5-(tri- fluoromethyl)pyrrole-3-carbonitrile; 4-Chloro-2-(3,5-dichloro-4-methylphenyl)-3-nitro-5- (trifluoromethyl) pyrrole; 2-(2-Bromo-4-chlorophenyl)-1-(2-propynyl)-4,5-bis-(tri- fluoromethyl)pyrrole-3-carbonitrile; 2-(2,5-Difluorophenyl)-3-nitro-4,5-bis-(trifluoro- methyl) pyrrole; . 5-(p- (Trifluoromethoxy)phenyl]pyrrole-2,4-dicarbo- nitrile; 5-(p-Dimethylaminophenyl)-4-nitropyrrole-2-carbo- nitrile; 3-Bromo-5-(p-chlorophenyl)pyrrole-2,4-dicarbonitrile; 4-Bromo-2-(p-chlorophenyl)-5-nitropyrrole-3-carbo- nitrile; 5- (p-Methylthiophenyl)=-3-(trifluoromethyl)pyrrole-2,4- dicarbonitrile; 1-Allyl-4-nitro-5-(a,a,a-trifluoro-p-tolyl)-3-(tri- fluoromethyl)pyrrole-2-carbonitrile; 4-Chloro-2-(p-chlorophenyl)pyrrole-3-carbonitrile; 2-(m-Methanesul fonylphenyl)-4-(trifluoromethyl)pyrrole -3-carbonitrile; 2-(3-chloro-4-methylphenyl)-1-methyl-3-nitro-4-(tri- fluoromethyl) pyrrole; 2-Phenylpyrrole-3,4-dicarbonitrile; 5- (p-Ethanesulfinylphenyl)-4-nitropyrrole-3-carbo- nitrile; 2-Bromo-5-phenylpyrrole-3,4-dicarbonitrile; 2-Chloro-5-(3,5-dichlorophenyl)-4-nitropyrrole-3- carbonitrile; 1-Benzyl-4-nitro-5-(p-chlorophenyl)-2- (trifluoromethyl) pyrrole-3-carbonitrile; 2-Chloro-5- (m-bromophenyl)pyrrole-3-carbonitrile;

} 2-Bromo-1- (p-chlorophenoxy) methyl-5-(p-chlorophenyl) -3-nitropyrrole; 2,4-Dibromo-5-phenylpyrrole-3-carbonitrile; 5- (p-Bromophenyl) -2,4-dichloro-3-nitropyrrole:;

2-Bromo-5- (3-bromo-4-methylphenyl)-1-(n-propyloxy) methyl-4-(trifluoromethyl)pyrrole-3-carbo- nitrile;

»-Bromo-5- (p-chlorophenyl) -3-nitro-4- (trifluoromethyl) pyrrole; 5-[m- (Difluoromethoxy)phenyl]-2- (trifluoromethyl) pyrrole-3-carbonitrile; 5-(2,3-Dichlorophenyl) -1-methoxymethyl-3-nitro-2- (trifluoromethyl) pyrrole; 4-Chloro-5-(g-napthyl)-2-(trifluoromethyl)pyrrole=3-

carbonitrile;

3-Bromo-2- (3, 4-dichlorophenyl)-4-nitro-5-(trifluoro- methyl) pyrrole;

5- (2-Bromo-5-ethylphenyl)-2, 4-bis- (trifluoromethyl) pyrrole-3-carbonitrile;

1-Ethyl-2- (p-fluorophenyl)-4-nitro-3,5-bis-(trifluoro- methyl) pyrrole;

1-[ (2, 6-Dichlorophenoxy)methyl]-5-(m-chlorophenyl) . pyrrole-2,3-dicarbonitrile; 3-Nitro-5(a,a,a-trifluoro-p-tolyl)pyrrole-2-carbo-

nitrile;

4-Chloro-5-(4-chloro-2-methylphenyl)pyrrole-2,3- dicarbonitrile;

4-Bromo-5-(3,4-dibromophenyl) -2-nitropyrrole-3-carbo- nitrile;

1-[ (1-Methoxy) ethyl]-5-(p-chlorophenyl)-4-(trifluoro= methyl) pyrrole-2,3-dicarbonitrile; 5- (p-Isopropylphenyl)-2-nitro-4- (trifluoromethyl) pyrrole-3-carbonitrile; 4-Chloro-5-(3,4-difluoromethylenedioxyphenyl)pyrrole= 3-carbonitrile;

Ce SO ( 3-Bromo-2-(3-chloro-4-cyanophenyl)-4-nitropyrrole; 1-{ (3,4-dichlorobenzyloxy)methyl]-2-(m-bromophenyl) pyrrole-4-carbonitrile; 2-(3,5-Dichloro-4-methylphenyl)-4-nitro-3-trifluoro- methylpyrrole; 2-Phenylpyrrole-3,4-dicarbonitrile; 2- (2-Bromo-4-chlorophenyl)-4-nitropyrrole-3-carbo- nitrile; . ” 2-Bromo-5-phenylpyrrole-3,4-dicarbonitrile; . 5-Chloro-2-(3, 4-dibromophenyl)-l1-methyl-4-nitropyrrole- 3-carbonitrile; 2- (p-Chlorophenyl-5- (trifluoromethyl) pyrrole-3,4- dicarbonitrile; 2- (o-Bromophenyl)-4-nitro-5-(trifluoromethyl)pyrrole-3- carbonitrile; 3-Bromo-5-(3-chloro-4-methoxy)pyrrole-2-carbonitrile; 3-Bromo-5- (m-bromophenyl)-2-nitropyrrole; 3,4-Dibromo-5-(3,4-dichlorophenyl)pyrrole-2-carbo- nitrile; 2-(3-Chloro-4-cyanophenyl)-5-nitro-3,4-dichloropyrrole; 3-Chloro-1-(p-methoxybenzyl)-5-(3,4-difluorophenyl)-4- (trifluoro-methyl)pyrrole-2-carbonitrile; 3-Bromo-5-(3,5-dibromo-p-tolyl)-2-nitro-4-(trifluoro- methyl) pyrrole; 1-(2,3,3-Trichloroally)-5-(p-chlorophenyl)-3-(trifluor- omethyl)pyrrole-2-carbonitrile; 2- (p-Iodophenyl)-5-nitro-4-(trifluoromethyl)pyrrole; 4-Chloro-5- (m-isopropylphenyl)-3-(trifluoromethyl) pyrrole-2-carbonitrile; 3-Bromo-1-methyl-2-(3-fluoro-4-methylphenyl)-2-nitro- 3-(trifluoromethyl)pyrrole; 5- (p-Bromophenyl) -1-isopropyl-3,4-bis- (trifluoromethyl) pyrrole-2-carbonitrile; 2-(3,4-Dichloro-4-methylthio)-5-nitro-3,4-bis-(tri- fluoromethyl) pyrrole;

. 5=-(m-Difluoromethoxyphenyl)pyrrole-2,3-dicarbonitrile: 5-(3-Bromo-4-cyanophenyl)-2-nitropyrrole-3-carbo- nitrile; 4-Chloro-1l-methoxymethyl-5-(p-bromophenyl)pyrrole-2, 3 dicarbonitrile: 4-Bromo-5-(2,6-dichloro-4-methylthio)-2-nitropyrrole-3- carbonitrile; 1-[ (p-Bromophenoxy) methyl ]-5-(m-trifluoromethyl) -4- (trifluoromethyl)pyrrole-2,3-dicarbonitrile; 5-(a-Naphthyl) -2-nitro-4~ (trifluoromethyl) pyrrole-3- carbonitrile; 4-Bromo-5-(3-bromo-4-trifluoromethylphenyl)pyrrole-2- carbonitrile; 3-Chloro-2-(2,3-dichlorophenyl)-5-nitropyrrole;

5-(m-Cyanophenyl)-3- (trifluoromethyl) pyrrole-2-carbo-

nitrile; 2-(3-Bromo-4-isopropoxy)-5-nitro-3-(trifluoromethyl)

pyrrole; 5-(p-Chlorophenyl)pyrrole-2,4~dicarbonitrile;

2-(3,4-Dichlorophenyl)-5-nitropyrrole-3-carbonitrile; 3-Bromo-5-(3,4-dichlorophenyl)pyrrole-2, 4-dicarbo-

nitrile;

} 4-Bromo-2-(3,4-dichlorophenyl)-5-nitropyrrole-3-

carbonitrile;

5-(3,4-Dibromophenyl)-3~ (trifluoromethyl) pyrrole-2,4-

dicarbonitrile; 2-(m-Chlorophenyl)-5-nitro-4- (trifluoromethyl) pyrrole-

3-carbonitrile; 5-Bromo-3-(3,5~-dichloro-4-difluoromethoxyphenyl)

pyrrole-2-carbonitrile; 2-Bromo-4-(2,5~-dibromophenyl)-5-nitropyrrole; 2,3-Dibromo-4-(p-chlorophenyl)pyrrole-5-carbonitrile; 2,3-Dichloro-4-(3,5-difluorophenyl)-5-nitropyrrole; 5S-Bromo-3-(p-chlorophenyl)-1-hydroxyethyl-4-(tri-

fluoromethyl)pyrrole-2-carbonitrile;

2-Chloro-5-nitro-3- (trifluoromethyl) -4-(m-trifluoro- methylphenyl) pyrrole; 3=(3-Bromo-4-chlorophenyl)-5- (trifluoromethyl) pyrrole- 2-carbonitrile; 3-(3-Chloro-4-fluorophenyl)-2-nitro-5- (trifluoromethyl) pyrrole; 4-Bromo-3-(p-chlorophenyl)-1-methylthiomethyl-5~(tri- fluoromethyl)pyrrole-2-carbonitrile: 3-(4-Bromo-3-cyanophenyl)-4-chloro-2-nitro-5-(tri- fluoromethyl) pyrrole; 4-(p-Chlorophenyl)-2,3-bis-(trifluoromethyl)pyrrole-2- carbonitrile; 3-(2,3-Dichlorophenyl) -2-nitro-4,5-bis- (trifluoro- methyl) pyrrole; 3-(3,4-Dichlorophenyl)pyrrole-2,5-dicarbonitrile; 4-(2-Bromo-4-methylphenyl)-5-nitropyrrole-2-carbo- nitrile; 3-Bromo-4-(3,5-dichloro-4-methylthiophenyl}pyrrole- 2,5-dicarbonitrile; 4- (m-Bromophenyl) -3-chloro-5-nitropyrrole-2-carbo- nitrile; 3-(p-Acetamidophenyl) -4- (trifluoromethyl) pyrrole-2,5- dicarbonitrile; ’ 4- (m-Bromophenyl) -5-nitro-3-(trifluoromethyl)pyrrole-2- carbonitrile; 4-Chloro-3-(3,4-dichlorophenyl)~1-(1l-propenyl)pyrrole- 2-carbonitrile; 3-Bromo-4-~(p-dimethylaminophenyl)-5-nitropyrrole; 1-(3,4-Dichlorobenzyl (-3-(p-chlorophenyl)-4-(trifluoro- methyl)pyrrole-2-carbonitrile; 2-Nitro-3-(p-tetrafluoroethoxyphenyl)-4-(trifluoro- methyl) pyrrole; 3-(3-Bromo-4-ji-propylphenyl)pyrrole-2,4-dicarbonitrile; 4-(p-Ethylsulfonylphenyl)-5-nitropyrrole-3-carbo- nitrile;

~ i . de - 11 - : 5 Bromo-1-(2-methoxyethyl)-4-(2,4,6-trichlorophenyl) pyrrole-2,4-dicarbonitrile; »-Chloro-4-(2,3-dichlorophenyl)-5-nitropyrrole=-3= carbonitrile; 3- (p-Fluorophenyl) -5- (trifluoromethyl) pyrrole=2,4- dicarbonitrile; 4- (p-Todophenyl) -5-nitro-2- (trifluoromethyl)pyrrole=3= carbonitrile; &_chloro-4-[p- (N-methylacetamido)phenyl]pyrrole-2- carbonitrile: 5 — Bromo-4- (o-bromophenyl) -1-propargylpyrrole-2-carbo= nitrile; »-Bromo-3- (o-bromophenyl)-5-nitropyrrole; + (p_Chlorophenyl) -3,5-dichloro=1-(2,3,3-trichloroally) pyrrole-2-carbonitrile; 3-Bromo-5-chloro-4- (p-chlorophenyl) -2-nitropyrrole; . - -Bromo-4-[p- (2,2-dichloro-1,1-difluoroethoxy) phenyl] _3— (trifluoromethyl) pyrrole-2-carbonitrile’ —chloro-3- (2-bromo-4-ethylthiophenyl) -5-nitro=4- (tri fluoromethyl) pyrrole; +- (3-Bromo-4-acetylphenyl) -5- (trifluoronethyl) pyrrole” 2-carbonitrile; : L-Cyano-3- (3, 4-dibromophenyl) -5-nitro-2- (Erifluore methyl) pyrrole: —Bromo-1-methoxymethyl-4- (trifluoromethyl) =5= (£ri- fluoromethyl)pyrrole-2-carbonitrile: +- (p-Chlorophenyl) ~4-iodo-5-nitro-2-(trifluoronethyl) pyrrole; + (n-Bromophenyl) ~1-( (1-ethoxy) ethyl) 3, 5-di= (EFLEIROX omethyl)pyrrole-2-carbonitrile; 1- (2-Bromo-4-methoxyphenyl) ~5-nitro=2, 4=dis (ErLEIRO¥E” methyl) pyrrole: +- (p-Chlorodi fluoromethoxyphenyl) pyrrole-2, 5-dicarbos nitrile: - (p-Tsobutyrylaminophenyl) -5-nitropyrrole-2-carbos nitrile; 3-Bromo-4-(3, 4-dimethoxyphenyl)pyrrole-2, 5-dicarbo- nitrile; 4-Chloro-3-(p-chlorophenyl)-1-isopropyloxycarbonyl methyl) -5-nitropyrrole-2-carbonitrile; 3-(o-Bromophenyl)4-(trifluoromethyl)pyrrole-2,5- dicarbonitrile; 1-(2-Chloroethyl)-3-(3,4-dichlorophenyl)-4-(trifluoro- methyl) pyrrole~2-carbonitrile; 4-(4-Bromo-3-trifluoromethoxyphenyl)-3-chloropyrrole-2- carbonitrile; 3-Bromo-4-(2,4-dichlorophenyl) -1-isopropyl-2-nitro- pyrrole; 4-(3-Methoxy-4-cyanophenyl) -3-(trifluoromethyl)pyrrole -2-carbonitrile; 1-(3,4-Dichlorobenzyl)~4-(2-methyl-4-iodophenyl})-2- nitro-3-trifluoromethylpyrrole; 1-Methyl-4-(3,5-di(trifluoromethyl)phenyl ]pyrrole-2,3- dicarbonitrile; 4-(3,4-Dichlorophenyl)-2-nitropyrrole-3-carbonitrile; 4- (m-Bromophenyl) -1-carbomethoxymethyl-5-chloropyrrole- 2,3-dicarbonitrile;

S-Bromo-4-(2, 6-dichloro-4-methanesul finylphenyl-2- ’ nitropyrrole-3-carbonitrile; 4-(p-Chlorophenyl)-1~(2,2,2-trifluoroethyl)-5-(tri- fluoromethyl)pyrrole-2,3-dicarbonitrile; 4-(3,5-Dichlorophenyl)-2-nitro-5- (trifluoromethyl) pyrrole-3-carbonitrile: 2-Chloro-4-(3-chloro-4-N-methylacetamidophenyl) pyrrole-3-carbonitrile; 2-Bromo-4-(3-bromo-4-n-propylphenyl)-3-nitro- pyrrole; 2,5-Dichloro-4-(3,5-dichloro-4-methylthiophenyl) pyrrole-3-carbonitrile; = 2,5-Dibromo-1-(2,4-dibromophenoxymethyl)-3-(p-chloro-

phenyl-4-nitropyrrole; 4-(3-Bromo-4-cyanophenyl)-2-chloro-5- (trifluoromethyl) pyrrole-3-carbonitrile; 2-Bromo-1l-methyl-3-nitro-4-(a,a,a-trifluoro-p-tolyl) pyrrole; 4-(p-chlorophenyl)-1-(n-butyloxymethyl)-5-(trifluoro- methyl) pyrrole~-3-carbonitrile; 4-(3,4-Methylenedioxyphenyl)-3-nitro-2-(trifluoro- methyl) pyrrole; 5-Chloro-4-(3-chloro-4-trifluoromethoxyphenyl)-2-(tri- fluoromethyl)pyrrole-3-carbonitrile; 2-Bromo-3-(3,4-dichlorophenyl)-1-ethylthiomethyl-4- nitro-S5-(trifluoromethyl)pyrrole; 4-[p-(tetrafluoroethoxy)phenyl}-2,5-di-(trifluoro methyl) pyrrole-3-carbonitrile; 3-(3-Bromo-4-acetoxyphenyl)-1-(3,4-dichlorophenoxy- : methyl) -4-nitro-2,5-di~ (trifluoromethyl) pyrrole; 4-(p-Bromophenyl)-1-( (2-methoxy)ethyl]pyrrole-2,3- dicarbonitrile; 4~-(m-Isopropionamidophenyl)-3-nitropyrrole-2-carbo- nitrile : 5-Bromo-4-(2-chloro-4-methylthio)pyrrole-2,3-dicarbo~ nitrile; 5-Chloro-4-(p-chlorophenyl)-1-hydroxyethyl-3-nitro- pyrrole-2-carbonitrile; 4-(3,5-Dibromo-4~cyanophenyl)-5- (trifluoromethyl) pyrrole-2,3-dicarbonitrile; 4-(4-Chloro-2-methylphenyl)-1~isopropylthiomethyl-3- nitro-5-(trifluoromethyl)pyrrole-2-carbo- nitrile; 5-Bromo-4-(3,4-dichlorophenyl)-1-(difluoromethyl) pyrrole-3-carbonitrile; 2-Chloro-3- (m-difluoromethoxyphenyl)-4-nitropyrrole; 1- (2, 4-Dibromophenoxymethyl) -4- (m-chlorophenyl) -5-(tri-

: : . Ce - Ceri

CY

. . ’ . - 14 - fluoromethyl)pyrrole-3-carbonitrile; 3-(3-Bromo-4-ethoxy)-4-nitro-2- (trifluoromethyl) pyrrole; 3-(2,4,6-Trichlorophenyl)pyrrole-2,4-dicarbonitrile; 3- (4-Bromo-3-chlorophenyl) -1-(difluoromethyl)-4-nitro- pyrrole-2-carbonitrile; 5-Bromo-3- (p-chlorophenyl) -1-(isobutyloxymethyl) pyrrole-3-carbonitrile; 3- (4-Bromo-3-methylphenyl) -5-chloro-4-nitropyrrole-2- carbonitrile; 3-(2-Naphthyl) -5- (trifluoromethyl) pyrrole-2,4-dicarbo- nitrile; 3-(3-Cyano-4-methylphenyl)-1-methyl-4-nitro-5-(tri- fluoromethyl)pyrrole-2-carbonitrile: 2,3-dichloro-5-(3,4-dichlorophenyl)-4-nitropyrrole 2-(3,5-dibromo-4-methoxyphenyl) -4,5-dichloropyrrole-3- carbonitrile; 2,3-dichloro-4-nitro-5-(2,4,6-trifluorophenyl)-4-nitro- pyrrole; 4,5-dibromo-2-(2,3,6~trifluorophenyl)-3-carbonitrile 4,5-dichloro-2-(3,4-dichlorophenyl)-1-(ethoxymethyl)- : pyrrole-3-carbonitrile; 4,5-dibromo-1-methyl-2-(a,a,a-trifluoro-p-tolyl) pyrrole-3-carbonitrile; 4,5-dichloro-2-(3,4-dichlorophenyl)-1-ethylpyrrole-3- carbonitrile; 2, 3-dichloro-4-nitro-5-[p-(trifluoromethoxy)phenyl]- pyrrole: 4,5-dichloro-2-[m-(trifluoromethoxy)phenyl]pyrrole-3= carbonitrile; 4,5-dichloro-2-(3,4-dichlorophenyl)-1-methylpyrrole=3- carbonitrile; 2,3-dichloro-5-(p-chlorophenyl)-1-methyl-4-nitro pyrrole; and

4-bromo-5-chloro-2-(p-chlorophenyl)-1-methylpyrrole-- : carbonitrile. >~chloro-2-(3, 4-dichlorophenyl)-4-fluoropyrrole-3- carbonitrile 27bromo-5-(p-chlorophenyl) -1- (ethoxymethyl) -4-fluoro- pyrrole-3-carbonitrile 3-bromo-5-(p-chlorophenyl)-2-fluoro-4-nitropyrrole

Certain novel arylpyrrole compounds of formula I, wherein A is hydrogen; w is CN and Xx, v, L,

M and R are as described above, can be prepared by reacting N-formyl-DL-phenyl-glycine or a substituted

N-formylphenylglycine represented by the structure formula VIII:

L oe - or (VIII)

M NHCH=Q

R wherein L is H, F, Cl or Br; R and M are each indepen- dently H, CC alkyl, C.-C alkoxy, C=C, alkylthio, - C.-C, alkylsulfinyl, C1 C4 alkylsulfonyl, cyano, F, C1,

Br, I, nitro, CF,, R,CF,Z, R,CO or NR,R, and when on adjacent positions and taken together with the carbon atoms to which they are attached, M and R may form a ring in which MR represents the structure: ~~ ~0CH,50-, -~0CF,0- or ; ye

Cond

Co | | oo fil 261 SC *T -— 16 -—

Z is S(O)n or 0; R, is H, F, CHF, CHFC1l or CF,; R, is : C=C, alkyl, c,-c, alkoxy or NR,R, ; R, is H or C,-C4 alkyl; R, is H, C,-C4 alkyl or RCO; R, is H or C,-¢, alkyl and n is an integer of 0, 1 or 2; with at least an equivalent amount of a 2-chloroacrylonitrile and two to three equivalents of acetic anhydride. The reaction is conducted at an elevated temperature, preferably about 70° to 100°C.

The reaction can be illustrated as follows:

L

" 0H rl Rc,0 4 hc + CHp=C+CN

R “\NHCH=0

CN

Bu

M

(VII) N

R

Conversion of the thus prepared 2-phenyl- pPyrrole-3-carbonitrile or 2- (substituted phenyl) pyr- role-3-carbonitrile to the corresponding formula II, 4-halo, 5-halo or 4,5~dihalo-2~ (substituted phenyl) pyr- . role-3-carbonitrile, is readily achieved by reaction of 22 the above said 2-phenylpyrrole-3-carbonitrile or 2- (substituted phenyl) pyrrole-3-carbonitrile with at least about 1 or 2 equivalents of a sulfuryl halide, bromine or chlorine, in the bresence of a solvent such as dioxane, THF, acetic acid or a chlorinated hydrocar- bon solvent. For preparation of a monohalo pyrrole-3- carbonitrile use of about 1 equivalent of the halogen- ating agent is required; whereas, preparation of a dihalo pyrrole-3-carbonitrile requires 2 to 3 equivalents of said halogenating agent. When sulfuryl chloride or sulfuryl bromide is used the reaction is generally conducted at a temperature below about 40°c and preferably between about 0° and 30°, but when elemental bromine is employed, the reaction is usually conducted at about 30-40°c. Other effective halogenating agents that may be employed in these reactions include sodium hypochlorite, t-butylhypo- chlorite, N-bromosuccinimide, N-iodosuccinimide and the like. The reaction may be illustrated as follows:

CN ¥ EN 1s SUN NL

N Bra, Clg, 50,¢X), H

H wae XN / . N (1p

The formula II carbonitrile compounds of the present invention may also be prepared from the reac- } tion of a substituted or unsubstituted benzoyl aceto- nitrile with a 2,2-di(c,-c, alkoxy)ethylamine in the ~ presence of an arcmatic solvent to form the a=(2,2-di- J (C,-C4 alkoxy)ethylamino) -g-cyano-(substituted)styrene _- which is then converted to the 2-(substituted-phenyl) - pyrrole-3-carbonitrile of formula II by reaction of 10 said g-3-cyano-(substituted)styrene compound with tri- fluorocacetic acid or with concentrated HCl at a temperature between about 20° and 40°c. The reactions may be graphically illustrated as follows:

. : BE Cl Se 26180 & -— 18 —

L

M 0

N\ 7

C + HaNCH,CHCOC, Hg),

A= cn

R

} Yo Solvent l0 H

EL

. X N .

Ro A 0-Rg

CF3C0,H or 15 HC1

CN

/ L

V7 = 20 h wherein R, is ¢,-C, alkyl and L, R and M are as de- scribed above.

Also in accordance with the present invention 25 formula II 3-nitro-2-phenylpyrrole and 3-nitro-2-(sub- stituted) phenylpyrrole compounds can be prepared by reaction of an a-nitroacetophenone or a substituted ao- nitroacetophenone with a 2,2-di(C,-C,-alkoxy)ethyl- amine. The reaction is generally conducted in the presence of an inert organic solvent preferably an ” aromatic solvent, at an elevated temperature to give an a=(2,2-di(c,-C,~ alkoxy)ethylamino)-g-nitrostyrene or a substituted @-(2,2-di(C,~C,~alkoxy)ethylamino)-g-nitro- ; styrene that is converted to the formula II 3-nitro-2- 315 phenylpyrrole or 3-nitro-2-(substituted)phenylpyrrole by treatment with a mineral acid such as hydrochloric

* - 19 - or hydrobromic acid. Reaction of the thus prepared © nitrophenylpyrrole with sodium hypochlorite in the presence of an inert organic solvent at a reduced temperature yields the formula II 2,3-dichloro-4-nitro- 5-phenyl or 5-(substituted)phenylpyrrole.

The above reactions may be graphically illustrated as follows: 4 L . a

N\

SA=

R

L

M .

NO

| A= N—CH,CHCOC Hs) 5 i

R H

Je or CF4CO,H

NO,

L

/ \ H

N

H cl NO,

R

L

: NaOCl / \ H

N

Cl H

R

(11>

In addition to the several methods described in the literature for preparing substituted and unsub- stituted benzoyl acetonitriles, surprisingly we have found that these compounds may also be prepared by reacting an appropriately substituted benzoyl halide with an alkali metal hydride and an alkyl cyanoacetate, 3 . 3 such as t-butyl cyanoacetate, to yleld the corresponding t-butyl (benzoyl or substituted benzoyl) cyanoacetate. These reactions may be graphically illustrated as follows:

L 0 L eh _C-0C(CHy), Eh

C-C1 + NaH + CH, C0-C-CO-0C(CH,),

Nc -

R R oN

A 8 C

The thus formed Cyanoacetate ester can then be converted to a substituted or unsubstituted benzoyl acetonitrile by heating the compound in toluene con- taining p-toluene sulfonic acid. The reaction may be graphically illustrated as follows:

L L y M

PTSA

CO-C-CO0-0C(CHy)g ——» c toluene Bl

R CN R CN

‘25

Examples of the t-butyl (benzyl and substituted benzoyl acetonitriles used in the above reactions are shown in

Tables below.

t-Butyl (benzyl and Substituted benzyl)cyanoacetates s L ” R EY | >

Oo

L M R mp C

H 3-Cl 4-Cl 91-94

H H 4-OCF , 81-84

H H 4-Br 113-115

H H 4-CF, 146-147

H H 4-F 98-100

H H 4-CN 127-128

H H 4-CF 4CH,0 136-139

H H 4-CH,SO, 127-129

H 3-F 4-F 91-94

H H 4-CH.S 117-119.5 © 28 3

H H 4-CHF ,CF,0 92-94 3-Cl 5-C1 4-CH,0 ——

© ‘ . - 22 -

Benzoyl Acetonitriles > L

C— CH,CN

L M R mp°c

H H 4-C1 128.5-129.5

H 3-Cl 4-Cl 105-107

H H 2-C 153-55

H H 4-OCF, 79-81

H H 4-CF, 44-45

H 2-Cl 4-C1 66-67

H H 3-Cl 80-83

H H 4-CN 126-128

H H 4-F 78-80 + 25 H H 4-50,,CH,, 129-132

H 3-F 4-F 74-75

H H 3-CF, 58-60

H H 4-CH, 103.5-106

H H 4-NO 119-124 2 3-C1 5-C1 4-OCH, _—

So pe } or - 23 -

Preparation of N-substituted formula I arylpyrroles can be achieved by reaction of the appropriately substituted formula I arylpyrrole, wherein A is hydrogen and L, M, R, W, X and Y are as described above, with an appropriate alkylating agent and a suitable base. For example, a brominated hydroxy-C,-C,-alkyl and potassium t-butoxide. This reaction provides an arylpyrrole having the same substituents as the starting material, but in addition is substituted on the nitrogen with hydroxy-C,-C, alkyl. In a similar reaction cyanogen bromide is substituted for the prominated hydroxy C,7C4 alkyl and yields the formula I arylpyrrole with a carbonitrile substituent on the nitrogen. The reactions may be illustrated as follows: x W L

M +

N 1) Br Cq-C4 alcohol + K'0-t-Bu

Shy + or

R 2>cnBr

X HL

M vb ‘

R wherein L, M, R, W, X and Y are as described for formula I above and A is 1) C,~C, alcohol or 2) CN.

nl CF by co - —— vs —_ 24 —-—

Preparation of 2-phenylpyrrole 3,4-dicarboni- © trile, 2-bromo-5-phenylpyrrole-3,4-dicarbonitrile and substituted phenyl derivatives thereof can be obtained by reaction of fumaronitrile with bromine in the pre- sence of a chlorinated hydrocarbon such as chloroform at an elevated temperature to yield bromofumaronitrile.

The thus formed bromofumaronitrile is then reacted with

N- (trimethylsilyl) methyl-5-methyl-benzene-thioimidate or a substituted derivative thereof, in the presence of hexamethylphosphoramide at an elevated temperature to yield the 2-phenylpyrrole-3,4-dicarbonitrile. Bromi- nation of the thus prepared 3,4-dicarbonitrile yields the 2-bromo-5~phenylpyrrole-3,4-dicarbonitrile or the substituted phenyl derivative if the substituted

N- (trimethylsilyl)methyl-5-methyl-benzene-thioimidate is used in the previous reaction. The reaction may be graphically illustrated as follows:

CN CN

= evs

NC (-HBr) NC Ar

NC CN *

L ~~ : 7 \ " HHPR/3 equiv. Ha0 5 L *-— INS ¥ (-THS ,~HBr ,-CH,SH) NW

R n :

Br,/CHCI,

NC CN

J f

Br Nit

R

The examples provided by way of illustration below utilize the schemes illustrated above and provide a means for preparing other compounds of the invention ~ which are not specifically described herein.

The arylpyrroles of the present invention are effective for controlling insects, acarina and nema- todes. These compounds are also effective for protect- ing growing or harvested crops from attack by the above-said pests.

In practice generally about 10 ppm to about 10,000 ppm and preferably 100 to about 5000 ppm, of the formula I arylpyrrole, which encompasses all of the arylpyrrole isomers of formulas II, III, IV, V, VI and

VII, dispersed in water or other inexpensive liquid carrier is effective when applied to the plants, the crops or the soil in which said crops are growing to protect said crops from attack by insects, acarina and/or nematodes. These compounds are also useful for protecting turf grass from attack by pests such as grubs, chinch bugs and the like.

The formula I arylpyrroles of this invention are also effective for controlling insects, nematodes and acarina, when applied to the foliage of plants and/or to the soil or water in which said plants are growing in sufficient amount to provide a rate of from : about 0.125 kg/ha to about 4.0 kg/ha of active ingre- dient. Obviously higher rates of application of the formula I arylpyrroles may be used to protect crops from attack by insects, nematodes and acarina, however, higher rates of application are generally unnecessary and wasteful.

While the arylpyrroles of this invention are effective for controlling insects, nematodes and acarina when employed alone, they may be used in combination with other biological chemicals, including other insecticides, nematicides and acaricides. For example, the arylpyrroles of this invention may be used

; . | ; Co a | yy - 26 - effectively in conjunction or combination with phos- phates, carbamates, pyrethroids, formamidines, chlori- nated hydrocarbons, halobenzoylureas and the like.

Advantageously, the above-said arylpyrroles may be formulated into dry compacted granules, flowable compositions, granular formulations, wettable powders, dusts, dust concentrates, microemulsions and the like, : all of which lend themselves to soil, water and/or foliage application and provide the requisite plant protection. Such formulations include the compounds of the invention admixed with inert, pharmacologically- acceptable solid or liquid diluents. . For example, wettable powders, dusts and dust concentrate formulations of the invention can be prepared by grinding together about 3% to 20%, by : weight, of the formula I arylpyrrole compound, with about 3% to 20% by weight of a solid anionic surfac- tant. One suitable anionic surfactant is a dioctyl ester of sodium sul fosuccinic acid, specifically

Aerosol OTB® surfactant marketed by the American

Cyanamid Company. About 60% to 94%, by weight, of an jnert solid diluent, such as montmorillonite, attapul- gite, chalk, talc, kaolin, diatomaceous earth, lime- stone, silicates or the like also is used in such formulations. compacted granules especially useful for soil or water application can be prepared by grinding together in about equal parts, usually about 3 to 20 parts, of the arylpyrrole and a solid surfactant, with about 60 to 94 parts of gypsum. Thereafter, the mixture is compacted into small granular particles, about 24/48 mesh or larger. other suitable solid surfactants useful in the present formulations include not only the anionic dioctyl ester of sodium sulfosuccinic acid but also nonionic block copolymers of ethylene oxide and propy- lene oxide. Such block copolymers are marketed by BASF

Wyandotte Corporation as Pluronic 10RS8®, 17R8®, 25R8®,

F38®, F68®, F77%® or F87®, and are especially effective for the preparation of compacted granules.

In addition to the powders and concentrate formulations described hereinabove, wettable powders and flowables may be used because they may be dispersed in water. Preferably, such flowables will be applied at the locus with the aqueous compositions being sprayed on the foliage of plants to be protected.

These sprays also may be applied to the breeding ground, food supply or habitat of the insects and acarina sought to be controlled.

Where solid formulations of the compounus of this invention are to be used in combination treatments : with other pesticidal agents, the formulations can be applied as an admixture of the components or may be applied sequentially.

Similarly, liquid formulations of the aryl- pyrrole in combination with other pesticidal agents may be tank mixed or may be applied separately, sequential- ly, as liquid sprays. Liquid spray formulations of the : compounds of the invention should contain about 0.001% to about 0.1% by weight of the active arylpyrrole.

The following examples are presented as illustrations of the present invention.

. | ~ “

Lk iB 26180 . 3 - 28 -

EXAMPLE 1 2-Phenylpyrrole-3-carbonitrile

CN

CO,H Cl / Ac,0 fA

CH + CHp=C-CN ——>

MNHCH=0

The following procedure is similar to the method given in JOC, 43, 4273-6 (1978). A magnetically stirred mixture of 30.00g of N-formyl-phenylglycine is heated at 90% for 1 & 1/2 hours. The clear yellow reaction solution is concentrated in vacuo to give 42.5g of an oily brownish orange semi-solid. Material partially purified by chromatography on silica gel is shown by the proton NMR spectrum to be a mixture of 73% 2-phenylpyrrole-3-carbonitrile and 27% 2-phenyl-3-cyano5-methylpyrrole. Recrystallization once from chloroform and twice from 1,2-dichloroethane gives 1.69g of an off-white solid which proton NMR shows it to be 96% 2-phenylpyrrole-3-carbonitrile, mp 148-152°C.

Microanalysis (MW 168.19): caled.: C, 78.55%; H, 4.79%; N, 16.66%

Found: Cc, 78.52%; H, 4.73%; N, 16.54% 3s

~ 29 -

EXAMPLE 2 4,5-Dichloro-2-phenylpyrrole-3-carbonitrile and 5- chloro-2-phenylpyrrole-3-carbonitrile

CN CN cl CN hoy S0,C1; Re VE Ln

N CH,Cl1, Cl N

H Cl N H

H

To a magnetically stirred ice-water cooled solution of 2.00g (11.9 mmol,) of 2-phenyl-3-cyano- pyrrole in 80 mL of methylene chloride is added drop- wise over a period of 5 min., 1.90 mL (3.19 9g, 23.6 mmol,) of sulfuryl chloride by means of a syringe.

Throughout the addition the temperature is kept between 5°c and 10°c. stirring at 5-10°C is continued for 90 a0 minutes. The reaction mixture js vacuum filtered to remove a precipitated solid (1.289) identified as 5- chloro-2-phenylpyrrole-3-carbonitrile, mp 192.5-195°C.

The filtrate is diluted with 400 mL of ethyl acetate, washed twice with 200 mL of water, dried (sodium 2s sulfate), treated with charcoal, filtered, and then concentrated in vacuo to give (after slurrying of the residue with hexane) 0.609 (21.3% yield) of a pink- purple solid. This solid is recrystallized from 5 mL of hot acetone to give 0.329 (9% yield) of 4,5-dichloro 130 _2-phenylpyrrole-3-carbonitrile as an orangish brown solid, mp 254-255°C.

Max (mull,Nujol): 3165 (br s), 3120(s), 2245(s), 1570(m), 1513 (m), 1440(s), 1252(m), 1069 (m), 996(m), 920(m), : 15 768(s), 698(s), 665 (8s) en-l. \

1 26180 - 30 - . H-NMR (DMSO): 67.73 (d, J=6.6Hz, 1.97H, two phenyl protons at c-2,6), 67.52 (t, J=7.3Hz, 2.04H, two phenyl protons at c-3,5), §7.44 (t, J=7.3Hz, 1.02H, one phenyl proton at C-4).

C-NMR (DMSO) : 6137.51 (C-2 pyrrole carbon), §129.25 (C-4 phenyl carbon), §129.04 (C-3,5 phenyl carbons), 6128.37 (c-1 phenyl carbon) §125.88 (c-2,6 phenyl carbons), ’ 10 §114.32 (either C-5 pyrrole or the nitrile carbon), 5114.14 (either C-5 pyrrole or the nitrile carbon), §110.72 C-4 pyrrole carbon), §89.78 (C-3 pyrrole carbon) .

Microanalysis (MW 237.09): calcd.: C, 55.72%; H, 2.55%; N, 11.82%; cl, 29.91%

Found : C, 55.78%; H, 2.59%; N, 11.12%; Cl, 29.74%

EXAMPLE 3 p-chloro-g-[ (formylmethyl)aminolcinnamonitrile. diethyl acetal 0 i. ? 3 ow + MH NCH,CHCOE UY, Le al HA) . 2 N 0 55 H N

A magnetically stirred solution of 250.00 g (1.39 mol,) of p-chlorobenzoylacetonitrile, 203 mL (185.95 g, 1.39 mol) of 2,2-diethoxyethylamine, and 1300 mL of dried toluene is heated at refux for 20 hours. Water is collected in a pean-Stark trap (23.8 mL, 95.2% theory). The hot cloudy dark brown solution with a large amount of undissolved solids is filtered through diatomaceous filter aid. After dilution with

- 31 =~ 200 mL of EtOAc, the solution is filtered through a 7cm . X 13.5cm column of silica gel. The filtrate is ~ concentrated in vacuo to give 354.38 g (86.4% crude yield) of a clear dark oil which slowly solidifies.

This solid is recrystallized from hot cyclohexane to give 324.269 (79.1% yield) of a waxy orange solid. NMR of this product shows it to be composed of 78% (2) and 23% (E) isomeric mixture of p-chloro-g-[ (formylmeth- yl)amino} cinnamonitrile, diethyl acetal, m.p. 60-72°C.

The following analytical data is for another similarly prepared sample.

Max (mull,Nujol): 3325(s), 3065(m), 2197(s), 1600(s), 1530(s), 1314(m), 1265(m), 1173(m), 1154(m), 1128(s), 1100(s), 1060(s), 1022(s), 939(m), 895(m), 844(s), 768(m), 730(m) cm-1.

H-NMR (chloroform): 57.47 (d, J=8.6Hz, 2.12H, two aromatic protons), 67.37 (d, J=8.6Hz, 2.12H, two aromatic protons), §5.10(E) & 64.86(2) (br t, 1.25H, one N-H proton], 64.69(Z) & 64.60(E) ([t, J=5.1Hz, 1.05H, one methine proton at the acetal carbon], 64.07 (E) & §4.05(2) (s, 0.83H, enamine g proton], §3.71(E) & 63.68(2) (gq, J=7.1Hz, 2.22H, two methylene protons of one of two ethoxy groups], 63.56(2) & 63.53(E) (q,

J=7.1Hz, 2.22H, two methylene protons of one of two ethoxy groups], §3.18 (t, J=5.1Hz, 1.77H, two methylene protons of the ethyleneacetal group), §1.20 (t,

J=7.1Hz, 4.90H, six methyl protons of the two ethoxy groups) .

C-NMR (chloroform): §161.21 (a-enamine carbon), 6136.29 (Z) & §134.60(E) [either C-1 or C-4 of the phenyl ring), 6134.08(Z) & 6132.30(E) [either C-1 or C-4 of the phenyl ring), 6§129.34(2Z) & §129.89(E) [either C-2,6 fod LJ + Uv - 32 - or C-3,5 of the phenyl ring], 6§128.94(Z) & §128.63(E) © [either C-2,6 or C-3,5 of the phenyl ring), 6121.19(2) & §119.50(E) [nitrile carbon], §99.43(Z) & §100.63(E) (f-enamine carbon}, 661.88(Z) & §63.25(E) [methine carbon of the acetal], §62.64(Z) & §63.03(E) [methylene carbons of the ethoxy groups}, 646.32(2) & 647.33(E) [methylene carbon of the ethyl amine group], 615.26 (methyl carbons of the ethoxy groups).

Microanalysis (MW 294.78): calcd: C, 61.11%; H, 6.50%; N, 9.51%' Cl, 12.03%.

Found: C, 61.25%; H, 6.25%; N, 9.34%; Cl, 12.35%.

EXAMPLE 4 2 (p-Chlorophenyl) -pyrrole-3-carbonitrile

CN i < CN . / 0—\ a4) + creo — { \ | HN aN N

H Cl

HW 294.78 MU 114.02 MU 202.64

To 108 mL of trifluoroacetic acid stirred at 23% is : : added 54.00 g (0.183 mol) of solid p-chloro-g-[ (formyl- methyl)amino]cinnamonitrile, diethyl acetal over a period of 45 minutes. This addition produced an exotherm to 38°C and, 32 minutes into the addition, a solid started to precipitate. After stirring at room temperature for 30 minutes, the reaction mixture is vacuum filtered and the collected solid is washed first with trifluoroacetic acid, secondly with an ethyl acetate-hexane mixture, and finally with hexane. The yield is 16.83 g (45.4%) of an off-white solid, mp 165-166°C. The following anal. data is from a similarly prepared sample.

Max (mull, Nujol): 3275(br ss), 2225(s), 1502 (s), 1410(m), 1275(m), 1200(m), 1108(s), 1023(m), 999(m), 908 (m), 843(s), 752(s), 722(s), 695(s), 620(s) cm-1.

H-NMR (acetone): §11.22 (v br s, 0.99H, one pyrrole N-H proton), 67.82 (d, J=8.9Hz, 2.46H, two aromatic phenyl protons), 67.51 (4d, J=8.9Hz, 2.46Hz, two aromatic phenyl protons), 67.02 (t, J=2.6Hz, 1.01H, one pyrrole proton at C-5), 66.58 (t, J=2.6Hz, 0.77H, one pyrrole proton at C-4).

C-NMR (acetone): §137.73 (pyrrole c-2), §134.42 (p-chlorophenyl at C-4), 6129.93 (methine carbons at

Cc-3,5 of the phenyl ring), 6128.07 (methine carbons at c-2,6 of the phenyl ring), §121.21 (pyrrole at C-5), §117.93 (nitrile carbon), 6113.78 (pyrrole carbon at

C-4), 690.86 (pyrrole carbon at C-3).

Microanalysis (MW 202.64): : Calcd.: C, 65.19%; H, 3.48%; N, 13.83%; Cl, 17.50%

Found: C, 64.18%; H, 3.52%; N, 13.63%; Cl, 17.74%

“oe - 34 -

Use of the above procedure as shown or with the substitution of concentrated hydrochloric acid for trifluoroacetic acid affords the following compounds:

CN

M

8 R

C3

H

M and/or R mp°C Acid Used 4-Cl 165-166 conc. HCl, CF ,COOH 3,4-di-Cl 216-221 CF ,COOH 2-Cl 156-157 CF ,COOH 4-0CF, 143-145 CF,COOH 4-CF, 179-180 CF,COOH 2,4-di-Cl 197-199 CF ,COOH 3-Cl 150-156 CF,COOH 4-CN 210-212 CF ,COOH 4-F 167-170 conc. HCl 4-SO,CH, 221-221.5 CF ,COOH 3,4-di-F 173-175.5 CF ,COOH 3-CF, 166-168 CF.,COOH 4~-COOCH, 155.5-158 CF, COOH 4-CH, 117-137 CF_ COOH 4-NO, 174-177 CF ,COCH 3S

. - . . “ i -— 35 -—

EXAMPLE 5 4,5-Dichloro-2-(p-chlorophenyl rrole-3-carbonitrile

CN ci. IN

Ee

N HORc N

H C1 Cl H Cl

To a mechanically stirred solution of 16.839 (83.1 mmol) of 2- (p-chlorophenyl)pyrrole-3-carbonitrile in 450 mL of glacial acetic acid at 36°C is added dropwise 14.7 mL (24.70 4g, 183.0 mmol) of sulfuryl chloride over a period of 18 minutes. The addition produces a slight exotherm to 39°c and, after another 16 minutes, the reaction mixture is vacuum filtered.

The collected solids are washed first with acetic acid and then with water. This solid after recrystalliza- tion from hot ethyl acetate, melts at 259-261°C. By similar procedures other samples of this product were prepared and the analytical data for one such product is shown below. ' 25

Max (mull, Nujol): 3170(br s)., 3100(m), 2225(s), 1508 (m), 1097 (m), 825(s), 717(m), 660(m) cm-1.

H-NMR (DMSO): d7.72 (4d, J=8.6Hz, 2.00H, two aromatic protons), 67.56 (d, J=8.6Hz, 2.00H, two aromatic protons) .

C-NMR(DMSO): 6136.01 (pyrrole C-2 carbon), §133.92 (p-chlorophenyl C-4 carbon), 6129.09 (p-chlorophenyl 33 c-3,5 carbons), §127.41 (p-chlorophenyl Cc-4 carbon),

§127.11 (p-chlorophenyl C-1 carbon), 6114.49 (nitrile carbon), 6114.10 (pyrrole C-5 carbon), §110.92 (pyrrole

C-4 carbon), §90.09 (pyrrole C-3 carbon).

Microanalysis (MW 271.54):

Calcd.: C, 48.65%, H, 1.86%; N, 10.32%; Cl, 39.17%

Found: Cc, 49.22%: H, 2.12%; N, 9.85%; C1, 39.03%

EXAMPLE 6 4,5-Dibromo-2-(a,e,a-trifluoro-p-tolyl) -pyrrole-3- carbonitrile :

CN

Br CN :

J — .

Br CF

H CFy rH 3

To a stirred mixture of 0.8g of 2-(a,a,a-tri- fluoro-p-tolyl)pyrrole-3-carbonitrile in 70 mL of chloroform is added 2 mL of bromine. The mixture, on stirring overnight, deposits a white solid which is collected by filtration. Thin layer chromatography (1:1 ethyl acetate-hexane) shows a single component; m.p. >230°C.

Anal. Calc'd for C,,Hg Br, FN, Cc, 36.55; H, 1.27; N, 7.11; Br, 40.61.

Found: C, 36.40; H, 1.08; N, 6.99; Br, 40.55.

Following the procedures of Examples 5 and 6, but substituting the appropriately substituted phenyl- pyrrole-3-carbonitrile for 2-(a,a,a-trifluoro-p-tolyl) 15 pyrrole-3-carbonitrile yields the following compounds.

X CN

L

$

Y M

N

FN

R

L M R x y mpc

H H 4-NO, Br Br 274-277

H H 4-F cr cl >220

H H 4-F Br Br 5220 H H 4-so,cH, Cl Cl 5230

H 3-F 4-F cr cl >230

H 3-F 4-F Br Br >220 2-Cl 3-Cl 4-Cl cl Cl 2-Br 3-Br 4-Br Br Br

H H 4-OCF, cl C1 222-225

H H 4-OCF, Br Br 231-232

H H 4-OCF, cl H }

H H 4-CN Br Br >230 : H H 4-CN cr cl >240

H H 4-S0,CH; Br Br >230

H H 4-NO, cl cl 246-249

H 3-Cl 4-C1l Br Br >260

H H 3-CF, cr cl >230

H H 4-cocH, Cl Cl 251-254

H 2,3-CH=CH- cl Cl 244-247

H H 4-CH, cl Cl 215-217

H 2-Cl 4-Cl Br Br >230 1s iil 26 vm Ao - 38 -

L M R Xx X mpc . H H 3-Cl cl Cl >230

H 2-Cl 4-Cl cl C1 >230

H H 4-C1 Br Br 273-274

H H 2-Cl Br Br >230

H H 4-cF, Cl Cl >230

H H 4-Br cl Cl >235

H H 2-Cl cl C1 >230

H 3-Cl 4-C1 cl Cl >235

H H H cl Cl 254-255

H H 4-C1 cl Cl 255-257

H H 4-CF, Br Br >230

H H 4-Cl Cl Br 262-263 (dec.)

H H 4-C1l Br Cl 250-258 (dec.)

H 3-Cl 5-C1l cl C1 >230

H 3-Cl 4-cl Cl Br >230 2-Cl 4-C1l 5-F cl cl 207-210

EXAMPLE 7 3-Nitro-2-phenylpyrrole

NO, i 2 enna, — 1) 55 )coaos + HaNCHpCHCOEL); — Cee NO, oe

NH-CH,CHCOEL), H

Alpha-nitro ‘acetophenone (5.7 9g, 0.0345mol) is taken up in 100 mL toluene and 4.69 (0.0345mol) of amino acetaldehyde diethyl acetal is added. The reactants are put into a 250 mL RB flask fitted with a

Dean-Stark trap. The trap is filled with 4A molecular i sieves and the mixture is heated at reflux for 18 hours. The toluene is removed in vacuo to give 8.36 g of s- (2, 2-diethoxyethylamino) -g-nitrostyrene as a brown oil. To this oil is added 50 mL of concentrated

HCl. As the flask is swirled the oil turns to a yellow suspension. After 10 minutes the solid is filtered to give 2.48 g of a yellow solid. Recrystallization from ether/ethylacetate/hexane gives the product as two fractions, 2.08 g of m.p. 190-192°, (31%).

Max 1485 em-* (No) , H-NMR (CDC1,/DMSO) 66.73 (m, 2H), 7.46 (m.5H) .

EXAMPLE 8 2,3-Dichloro-4-nitro-5-phenylpyrrole 7 \ + NaOCl —> J \

N —

N Cl H

H \ /

A mixture of 3-nitro-2-phenylpyrrole (1.569, 0.0083mol) in 60 mL of dioxane is cooled in an ice bath 25 . . , while 25.99 (.0182mol) of commercial sodium hypochlor- ite is added dropwise. After stirring for 45 minutes, the mixture is acidified with concentrated HCl. Water and Et,0 are added. The layers are separated and the 3 top organic layer is washed with H,0, dried over anhy- 0 ’ drous Mgso, and concentrated in vacuo to give 2.21g of yellow solid. Purification by chromatography using silica gel and eluting with increasing ratios of ethyl acetate/ hexane gives, after stripping, 0.77g of yellow 1s solid (36%) m.p. 190-190.5°C;

Analysis: Calcd. for C10H6N50,CL, C, 46.72; H, 2.35; N,

10.90

Found: Cc, 46.96; H, 2.867 N, 10.02

Following the procedures of Examples 7 and 8 above but using the appropriately substituted e-nitro- acetophenone and 2,2-di(c,-C, alkoxy) ethylamine yields the substituted a-(2,2-4i(C,-C, alkoxy) ethylamino) -8- nitrostyrene which is then converted to 3-nitro-2-(sub- stituted) phenylpyrrole by treatment with HCl, HBr or

CF,CO,H. Reaction of the thus formed substituted } phenylpyrrole with sodium hypochlorite in dioxane yields the chloro analogs; whereas, reaction of the substituted phenylpyrrole with bromine in chloroform yields the bromine analogs. 15 .

X NO,

L y \

N

H ™

R o

L M R X X mp C

H H H Cl Cl 190-190.5 : 25

H 4-C1 H cl Cl 214-215

H 4-C1l H Br Br 203-204 (dec.)

H H H Br Br 148.5-149 3-C1 4-C1l C cl cl 219-220 (dec.)

H 4-Br H cl cl 222-223 (dec.)

H H 4-CF, cl Cl 166-168

Chen en ee rene So Cw LE ae - 41 -

EXAMPLE 9 4,5-Dichloro-2-(3,4-dichlorophenyl)-1-methyl-pyrrole-3= carbonitrile

Cl CN c1 on ci} c1 + Hel + KOC(CHpy —> cf °N

Me Cl 10 .

In a 100 mL flask, 2 g of 4,5-dichloro-2-(3, 4-dichlorophenyl)pyrrole-3-carbonitrile in 60 mL dry

THF gives a clear brown solution. 1 eq of KOtBu is added w/ stirring, this giving a clear solution after a few minutes. 1 eq of MeI is added by syringe and the solution is heated at reflux for 4 hours. It is then left to stir at RT overnight. The following day 50 mL of H,0 is added and the mixture extracted with 4 x 50 mL CHCl, . The organic phases are combined, dried with

MgSO, , and concentrated. The resulting white solid is purified by flash chromatography on silica gel, using 50/50 EtOAc/hexane as an eluent. This gives 1.80 g of } a white solid.

Yield = 86% m.p. = 154-156 deg. C

Following the above procedure but substitut- ing the appropriately substituted phenylpyrrole-3-car- bonitrile or 3-nitro-2- (substituted)phenylpyrrole for 4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole-3-carboni- trile yields the compounds shown below.

~ . = Lv Po oo LoL es a Le jt fg eee tia eee ge Se Bh fu PL : : CORSIETTLT SAMTIGER SI

CF ol Se CARR Ly 75 ue iG pol

Lee : SR - - sr peg? MES pera

Cadel he TEE 2618¢C oT v — 42 —_— hy

R

A L M R XxX X mp°c

CH, H H 4-Cl cl Cl 152-153

C,H OCH, H 3-C1 4-Cl cl Cl 128-130

C,H H 3-Cl 4-Cl cl C1 137-138

CH, H 3-C1 4-Cl cl Cl 154-156

CH, H H 4~CF, Br Br 145-146

C H~CH, H H 4-CF, Br ‘Br 145-147

C HCH, H 3-Cl 4-C1 cl Cl 95-96

CH,=CH-CH, H 3-cl 4-C1 c1 cl 69-70

CH,=C-CH, H 3-Cl 4-Cl ci cl cl

CH=C-CH, H 3-Cl 4-Cl cl Cl 147-148 : . CH,SCH, H 3-Cl 4-Cl cl cl

C(CH.,) H H 4-CF cl cl 3/3 3

CH, H H 4-CF, cL cl 99-100

CHSC, H H 3-Cl 4-Cl c1 cl 74-75 0

C,H -OC-CH, H 3-Cl 4-Cl cl Cl 118-120 10 CH -OCH, H H a-cr, c1 cl 99-100

CH, H H 4-OCH,, Br Br 112-115

CH, H H 4-Cl Br Br 197-201 - 6-47

C,H OCH, H H 4-OCF , c1 cl 4

CH, H H 4-OCF cl Cl 72-73 - - oil 1s C Hg~CH, H H 4-OCF , cl ci

C,H OCH, H H 4-Cl Cl Cl -

- 43 =

A L M R XxX x mp°c ‘HOCH, CH, H 3-Cl 4-Cl Cl Cl 143-145

NC H 3-Cl 4-Cl Cl Cl 251-252

Cells CH, OCH, H 3-Cl 4-C1 Cl Cl 88-89

Cl O-CH, H 3-Cl 4-Cl1 Cl Cl 118-120

IC=C-CH, H 3-Cl 4-C1 Cl Cl 115-116

CH, H H 4-C1 Br CF, 126-129

C,H OCH, H H 4-C1 Br CF, 91-92

C,Hg-OCH,, H 3-C1 4-C1 Cl Cl 118-120

C,H -OCH, H H 4-Cl Br Br 104-105 : CeHgs—CH, H H 4-C1 Br Br 81-82

CH, H H 4-C1l ~ Br Br 197-201

CN H H 4-CF, Cl Cl 138-139

C,H -OCH,, H H 4-CF, Br CF, 104-105

C,H -OCH, H H 4-CF, H CF, 76-77

C,H OCH, H 3-Cl 4-Cl1 Br CF, 80-81

EXAMPLE 10 1-Benzyl-4,5-dibromo-2-(s,e,a~trifluoro-p-tolyl) pyrrole-3-carbonitrile

Br CN

Br cy Tn 7 + KOC(CHyY 5 + a — gn N oF

AAA 4

In a 100 mL flask, 1.5 g of 4,5-dibromo-2~ (a,a,a-trifluocro-p-tolyl)pyrrole-3-carbonitrile is mixed with 50 mL dry THF to give a clear dark solution. 1 eq of KOtBu is added with stirring. After a few minutes the solution clears. Benzyl bromide (0.65 q) is added by syringe. The mixture is heated at reflux overnight. The following day TLC (50/50 EtOAc/hexane)

: ee Ceara oy gaa

CTI eee LSE LT a oo CT nn JE RNR 26180 - 44 - 8 indicates the presence of both starting material and . product. The reaction is worked up in the following manner; 50 mL of water is added and the mixture is extracted with 4 x 50 mI CHCL,. The organic phases are combined and washed with 4 x 50 mL 10% ag. NaOH. The organic phase is dried with Mgso, and stripped. This gives a brown solid which is crystallized from EtOAc/ hexane.

Yield = 0.75g = 40.7% m.p. = 145-147 deg.C dec.

EXAMPLE 11 4.5-Dichloro=2-(3,4-dichlorophenyl)-1-(ethoxymethyl) - pYrrole-3-carbonitrile

C1 CN cl CN 7

Moy KOC(CH3)3 + CICH,0C,Hg — Ao. ctv NM cl

CHa0CHs

Cl

A sample of 4,5-dichloro-2-(3,4-dichlorophen-

Yl)pyrrole-3-carbonitrile (1.09, 0.003 mole) is dis- solved in 10 mL of dry tetrahydrofuran. To this solu- tion is added potassium t-butoxide (0.37g, 0.0033 mole) followed by chloromethyl ethyl ether (0.312g, 0.0033 mole). The mixture is stirred for about 1 hour at room temperature and then poured into a large volume of water precipitating the product. The white solid is collected and dried to give 1.09 (91%) with m.p. 128- 130°. Y ” , '

~ 45 -

EXAMPLE 12 : 4-Chloro-3-cyano-2-(p-chlorophenyl)pyrrole > cl CN ct CN

CN BR ) BR { § ~ HE NOC ne Aer He h cl 3

To a magnetically stirred 20°C solution of 17.87g (88.2 mmol, 1.00eq) of 2- (p~chlorophenyl) -3- cyanopyrrole in 800 mL of dioxane is added dropwide 250.15g (13.139 real, 176.4 mmol, 2.00eq) of 5.25 weight % bleach over a period of 30 minutes. After stirring at room temperature for a further 30 minutes, the reaction solution is poured into 2200 ml. of water.

The resulting mixture is vacuum filtered to remove a small amount of a black solid. The filtrate is acidified to pH 2 with concentrated HCl to produce a brown solid. This solid is vacuum filtered and the collected solids washed with water to give 22.419 of a brown solid. This solid is treated with 100 mL of 5% aqueous sodium hydroxide to dissolve the bulk of the material while leaving a small amount of undissolved black solid. This black solid, dissolved into 100 mL of ethyl acetate, is washed with 75 mL each of 5% aqueous NaOH, water, and sat. aqueous NaCl. The ethyl 10 acetate layer is dried (MgSO) treated with charcoal, filtered, and then rotary evaporated in vacuo to give 1.109 (5.3% yield) of an orangish brown solid. This solid is recrystallized from an ethyl acetate chloro=- form mixture to give 0.51g (2.4% yield) of an off-white 15 solid of 4-eloro-3-cyano=2- (pel orophenyl) PITEEE mp 251-253.5 C.

ht a ¢ LH

Sy we IT eR , ort Cy , oo ie ue — 46 —

EXAMPLE 13 . Preparation of S-bromo-2-(3,4-dichlorophenyl)pyrrole-3- carbonitrile

CN CN

Di / \ + Br, Loxane / \

N N

B

H cl r cl

Cl Cl

A sample of 2-(3,4-dichlorophenyl)pyrrole-3- carbonitrile (2.0gq., 0.008 mole) is dissolved in 100 mL of dioxane by warming to 40-50°. Then the solution is cooled to 30°C and bromine (1.3g, .o008 mole) is added.

After stirring 1 hour at room temperature the solution is poured into water and a gray solid (2.29, 88%) is collected. The mp is 233-236, decomposition.

In a similiar fashion one can prepare 5-bromo-2-~(3,4-dichloro)-3-nitropyrrole starting with 2-(3,4-dichlorophenyl)-3-nitropyrrole.

oo Co , - | CT Coo EERE ee meme te meee 2 Lan Came BEES gn - 47 - nt EXAMPLE 14

Preparation of 5-bromo-4-chloro-=2-(3 4-dichlorophenvyl) - pyrrole-3-carbonitrile

CN C1 CN 7\ + (CHg)aCOCL ~~ / \

N N or” N cl Bru cl . cl Cl

A sample of 5_bromo-2- (3, 4-dichlorophenyl)- pyrrole-3-carbonitrile (0.1589, 0.005 mole) is dissolved in tetrahydrofuran (5 mL). An equivalent amount of t-butyl hypochlorite is added and the solution stirred overnight. The solution is poured into water and the precipitate (0.0529, 30%) is collected. The mp is >275°C.

In a similiar fashion one can prepare » _bromo-3-chloro-5- (3, 4-dichlorophenyl) -4-nitropyrrole . py starting with »-promo—5-(3,4-dichlorophenyl)-4- nitropyrrole. \

oo ™ 26180 & . 3 —_ 48 —

EXAMPLE 15 . Preparation of 5-bromo-4-chloro-2-(p-chlorophenyl) - : pyrrole-3-carbonitrile

Cl CN c1 CN / + Br —_—

A 2 CHCl, / \

H cl Br” MN

H cl

To a magnetically stirred 22°c solution of 0.17g (0.67 mmol., 1.00 equivalent) of 4-chloro-2-(p- chlorophenyl)pyrrole-3-carbonitrile in 100 mL of chloroform is added dropwise over a period of 30 minutes, a solution of 0.20 mL (0.62g, 3.88 mmol., 5.79 equivalent) of bromine in 5 mL of chloroform. The addition produces no exotherm. After stirring at room temperature for 3 1/4 hours, the clear red reaction solution is. evaporated in vacuo to give 0.28g of an off-white solid. This solid is slurried with a hexane- methylene chloride mixture to give on vacuum filtration . 0.23g of an off-white fluffy solid. mp 262-263°C: dec.

ro . oo IE Conk mi Co RR

Co oe : SE re

Ce oo Cntr —- 49 -—_

EXAMPLE 16

Preparation of 5-chloro-4-bromo=-2-(p-chloro henyl) - pyrrole-3-carbonitrile

CN Br CN + Br, —— 7 \ 2 CHCl I \

N

N Cl

H cl H cl Cl

To a magnetically stirred 45°C solution of '1.00g (4.22 mmol., 1.00 equivalent) of s-chloro-2-(p- 1s chlorophenyl)pyrrole-3-carbonitrile in 300 mL. of chloroform is added dropwise over a period of 30 minutes, a solution of 0.40 mL (1.249, 7.76 mmol., 1.84 equivalent) of bromine in 25 nL. of chloroform. The addition produces no exotherm and towards the end of the addition, a small amount of a solid starts to precipitate. After stirring at room temperature for 19 1/2 hours the reaction mixture is evaporated in vacuo : to give 1.49g of an orangish white solid. This solid is slurried with a hexane-methylene chloride mixture to give on vacuum filtration 1.33g (100% yield) of a fluffy white solid. mp 250-258°¢C, dec.

AEE TERT RT gh me CT een

Sa A ae Cr RR SEE 26180 -— 50 -— : EXAMPLE 17

Preparation of S-chloro-2- —chlorophenyl)pyrrole-3- carbonitrile

CN CN i! \ + S0,Cl, _HORe 7 {

N N

Cl Cl H cl

To a 35°% magnetically stirred solution of 2.409 (11.8 mmol., 1.00 equivalent) of 2=(p-chlorophen-

Yl)pyrrole-3-carbonitrile, and 65 mL of glacial acetic acid is added dropwise by syringe 0.75 mL (1.26g, 9.34 mmol., 0.79 equivalent) of sulfuryl chloride over a period of 5 minutes. Approximately 5 minutes after the completion of the addition, a solid precipitated out of the reaction solution. After stirring at room tempera- ture for 45 minutes, the reaction mixture is filtered and the collected solid is washed well with cold acetic acid to give 2.08g (74% crude yield) of an off-white solid. This solid is recrystallized from 75 mL of hot acetic acid to give 1.63g (58% yield) of 97 wt$% pure.

Product mp 258.5-261°C.

EXAMPLE 18

Preparation of 2-(3,4-dichlorophenyl)-1-methylpyrrole- -3-carbonitrile

CN CN hs + KOC(CHydy + CHal —> Af

N N

H cl bg cl

In a 100 mL flask, 2.0 g of 2-(3,4-dichloro- phenyl) pyrrole-3-carbonitrile is dissolved in 50 mL of dry THF and 1 equivalent of potassium t-butoxide is added. This gives a slightly cloudy solution. One equivalent of methyl jodide is then added to the mixture by pipette. This leads to a slight lightening of the colour. A drying tube is attached to the flask and it is left to stir at ambient temperature overnight.

The next morning there is a slight 1light- i coloured precipitate in the flask. 50 mL of water is then added and the solution becomes clear before a solid precipitates out of the solution. This solid is filtered out of the solution and compared to the starting material by TLC (25% ethyl acetate/hexane) .

This indicates a new single spot which is faster moving than the starting material. It is dried in a vacuum oven at 50 deg. C overnight. The product yield is 1.31g or 62% yield and has a melting point of 140-142°cC.

Le Eee oo .. 261g 0 4 ’ EXAMPLE 19

Preparation of 4,5-dichloro-2-(3,4-dichlorophenyl)-1- methylpyrrole-3-carbonitrile

CN Cl CN

N N ci cr cl

CH, CH,

In a 50 mL round bottom flask, 0.59 of 2-(3, 135 4-dichlorophenyl)-1-methylpyrrole-3-carbonitrile is mixed with 35 mL of glacial acetic acid. The mixture is warmed slightly with a heat gun to dissolve all of the pyrrole.

To this clear solution is added 2 eq. of sulfuryl chloride by pipette. The solution is left to stir at room temperature for 12 hours.

After 12 hours the solution is poured into 50 mL of water, resulting in a white precipitate. This is filtered out and dried in a vacuum oven at 50°C for 3 hours.

The resulting solid is identical by TLC, (25% ethyl acetate/ hexane), and infrared analysis to the product of Example 9. Product yield is 0.36 (56%).

be eee RR REE pa TA GE ie Ge nee

CUTER Ge TRE MARL Ce AE REE ‘ - 53 - : EXAMPLE 20 preparation of 4,5-Dichloro-2-(3,4-dichlorophenyl)=l= (2-hydroxyethyl) -pyrrole-2-carbonitrile

C1 CN

C1

Jy + BrCICHOH + K*0F t-Bu — " cl c1 CN : c1 ey

C1 1s \

OH

To a stirred mixture of 2.0 g (6.5 mmol) of 4, 5-dichloro-2-(3,4-dichlorophenyl) -pyrrole-3-carboni- trile and 0.88 g (7.8 mmol) of potassium tert-butoxide heated at reflux in 50 mL of dioxane is added 0.98 g (7.8 mmol) of bromoethanol. The mixture is stirred at reflux for 12 hours, cooled, diluted with 50 mL of water, and extracted several times with chloroform.

The combined chloroform extracts are dried over magnesium sulfate and concentrated in vacuo to leave a solid which, on warming and dissolving in ethyl acetate, deposits on cooling mostly starting pyrrole.

Concentration of the mother liquor and recrystalliza- tion of the residual solid from 20% ethyl acetate in hexane gives 0.31 g of a white solid, mp 143-145°¢C; IR 5077A.

Anal. Ccalc'd for CigHa3NO, 7 c, 44.57, H, 2.29; N, 8.00; Cl, 40.57. 33 Found: (Agm 33139): C, 44.77; H, 2.29: N, 8.06; Cl, 40.14.

Lr eke GEES AT ar IT aera © eli oo

Cap WTA TT Ren LEE UUREEET a dn a BR EA men tT Sey Lee RE ET ACA a aH 1 : we rn Tr ee ee + Ligh CETTE es we RE

Sr Cane a oA Ta Te ENE EB A a oo Co SI Se Te one CA . do LTT CelEL LLL Ra

Ca oo oT TTEe magne he Ca en EAR pA 2618 ; - 54 -

EXAMPLE 21 preparation of 4,5-dichloro-2-(3,4-dichloro henyl pyrrole-1,3-dicarbonitrile c1 CN

A c1 c1 N CNBr + K't-BuD~ ~H c1

C1 CN :

MN | c1 ’ c1

N

C1

CN

Potassium t-butoxide (617 mg, 55 mmol) is added in portions to a solution of 3-cyano-4,5-dichloro 2-(3,4-dichlorophenyl)pyrrole (1.52 g, 5 mmol) in anhydrous THF (20 mL).. After 30 minutes, a solution of cyanogen bromide (583 mg, 5.5 mmol) in THF (1 mL) is added. The reaction mixture is stored at room temperature overnight. The solvent is removed in a rotary evaporator. The residue is treated with water and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride and dried (MgSO) . Evaporation and crystallization of the residue from ethyl acetate gives while crystals (1.07 4); mp 250.5-252.0°C; IR (nujol) 2255, 2245 em” tT (CN): 13. yMr (DMSO-dg) 102.7 (N-CN), 113.7 (3-CN) ; Mass spectrum 331.9 (M+1) . « . .

Anal. calc'd for C,,H4CP,N, (330.99); C, 43.54; H, 0.91; N, 12.7%; Cl 42.85. }

Found: C, 4362; H, 0.93, N, 12.63; Cl 41.95.

Ce hale a Re TL EL os Ce CE co THe GR TL Cr ela ‘ - 55 -

EXAMPLE 22

Preparation of 4,5-Dichloro-2-(3,4~-dichlorophenyl)=-1- {3-iodo-2-propynyl) -pyrrole-3-carbonitrile 3 C1 CN

A | c1

C1 MT +1, + NaOH

L C1 ‘\ C1 CN

N

C1

Ci N

C1 "ent

To a stirred mixture of 1.91 g (5.5 mmol) of 4,5-dichloro-2-(3,4-dichlorophenyl)-1-(2-propynyl) - pyrrole-3-carbonitrile in 500 mL of methanol is added 69 mL of 10% aqueous sodium hydroxide and then 0.70 g (2.7 mmol) of iodine. The mixture is stirred for 12 . hours and then acidified and diluted with 200 mL of water. The precipitated solids are collected and recrystallized from methanol to afford 0.51 g while crystals, m.p. 115-116°cC.

This reaction is also applicable to the conversion of any of the formula III, IV, V, VI or VII substituted N-alkynylarylpyrroles of the present invention to N-substituted 3-iodo-2-propynyl arylpyr- roles of said invention.

. : oe A ae

CT Ee NE &p

EXAMPLE 23

Preparation of 2-(3 4~dichlorophenyl) -4 5-diiodopyr- role-3-carbonitrile

CN I CN

0 cl A cl + THF I

N N-1I — N . Cl Cl 0

N-iodosuccinimide (5.7 g, .0254 mol,) is added slowly to a solution of 2-(3,4-dichlorophenyl) - pyrrole-3-carbonitrile (3.0 g, .0127 mol) in 100 ml of

THF. The reaction is stirred several hours at 25° until thin layer chromatography (silica gel; 100:100:1- ether:petrolium ether:acetic acid) shows completion.

The mixture is evaporated in vacuo to give a residue . containing the pyrrole and succinimide. The crude solid is dissolved in 500 mL of ether and shaken with § oe

X 400 mL of water to remove the succinimide. The ether is dried over Na,so, and evaporated in vacuo to leave 2.0 g (32.3%) of a grey-brown solid with mp >230° (loses purple vapors).

i nd SER FIRE

CT meee EE LTE Re — 57 —_

EXAMPLE 24

Preparation of 2-phenyl-1-pyrroline-4-carbonitrile

NC

° CN AD mol% nBu,N*F~ By =/ + THs —/ —_—

THF 716hr/RT 2

N

N

A solution of acrylonitrile (0.65 mL; 0.01 mol) and N- (trimethylsilyl) methyl-s-methyl-benzeneth jo. : imidate (2.4 g; 0.01 mol) in THF (100 mL) is cooled to -5°C in an ice-acetone bath. Under a nitrogen purge, a solution of tetrabutylammonium fluoride (1.0 mL of al

N solution in THF) and THF (20 mL) is added dropwise ' over 30 minutes The solution is stirred another 30 minutes at -5%, and then allowed to warm slowly to ambient. Stirring is continued another 18 hours, and then solvent is removed under reduced pressure. The residue is Partitioned between ether/water and the water layer extracted with fresh ether. The combined organic layer is washed with water, then saturated sodium chloride. The solution is dried over Mgso,, and ’ cooling the filtrate causes precipitation of an off- white solid (1.2 g:; 70% theoretical yield) whose spectral characteristics are identical to the material described by Tsuge [J. Org. Chen. 52, 2523 (1987).

Calcd. for C11H10N,: C, 77.65; H, 5.88; N, 16.47.

Found: «¢, 77.55; Hu, 5.83; N, 16.39. mp = 95-97%.

~- 58 -

EXAMPLE 25

Preparation of 2-phenvl-pyrrole-s-carbonitrie

NC NC

_ D0Q/DME pyr / \

N Te ort OW

Under a nitrogen purge 2,3-dichloro-5,6-di- cyano-1, 4~-bonzoquinone (0.23 g; 0.001 mol) and 2-phenyl =!-pyrroline-4-carbonitrile (0.17 g; 0.001 mol) is dissolved in 1,2-dimethoxyethane (13 mL) to form a

Clear orange solution. Pyridine (0.08 mL; 0,001 mol) is added in a single portion, causing a slight exotherm (to ca. 28°) and an immediate formation of a green/ grey precipitate. The suspension is stirred at room temperature for 18 hours during which time much of the solvent evaporates. The brownish semi-soliq residue is partitioned between ether and a half-saturated solution : of sodium carbonate. The red-brown aqueous layer is extracted twice with ether and the combined ether layer is washed with fresh water, then saturated sodium chloride. After drying with Mgso,, solvent is removed under reduced pressure to obtain a white semi-solid.

This material was recrystallized from ethylene dichloride (DARCO treatment) to yield lavender crystals (0.1 g).

The identical product is obtained directly in a single step by condensing a-chloroacrylonitrile and

N-(trimethylsilyl)methyl-S-methyl-benzenethioimidate pA Sa heii + BE SEA ey

SEE GEO SREY ET pe IRR a . : - - FE tok hh

SEE Ta Ce iy

CREAR eRe Le Co wo BE or rE RE ei ee . eh Cpl Beet — 59 -_ using tetrabutylammonium fluoride catalysis (analogous

J . { to the preparation of 2-phenyl-1-pyrroline-4-carboni- trile described previously).

Calcd. for Cy,HgN,? c, 78.57, H, 4.76; N, 16.67.

Found: C, 78.65; H, 4.70; N, 16.43. m.p. - 155-158°C.

EXAMPLE 26

Preparation of 2,4-dibromo-5-phenyl pyrrole-3-carbo- nitrile

NC NC Br / \ Bro/CHCl, / \ : _>

NH ~ Br NH :

Under a nitrogen purge, a solution of bromine (0.6 mL; 0.012 mol) in CHCl, (5 mL) is added dropwise 55 over 20 minutes to a stirring solution of 2-phenyl- pyrrole-4-carbonitrile (0.84 g; 0.05 mol) in CHCl, (20 mL). The resulting solution is stirred 18 hours at room temperature, then solvent is removed under reduced pressure to obtain a solid which is recrystallized from

C,H,Cl, (DARCO treatment), yielding the desired final product (0.6 g), m.p. = 239-242.

Calcd. for C11HeBIN,: Cc, 40.49; H, 1.84; Br, 49.08;

N, 8.59.

Found: C, 39.88; H, 1.87; Br, 48.81; N, 8.48.

Ea : 5 EEE Fo Co ; ER Re i Re me AU Ca leh he nS SOREN — 261s - 60 -

By the procedure described in Example 24, 25 and 26, 2, 4-dibromo-5-(p-chlorophenyl)pyrrole-3-carbo- nitrile, m.p. 270-272°C (dec.) is also prepared.

EXAMPLE 27 3',4'-Dichloro-3-(1,3-dioxolan-2-yl)-propiophenone

Cl CO,K A THF or i - + BrMg 0

Cl 0

C1 1 a oN

Cl

To a rapidly stirring mixture of magnesium turnings (0.64 g, 26 mmol) in 10 mL of tetrahydrofuran at 25°c in a 100 mL three-neck round bottom flask equipped with a thermometer, a 60 mL addition funnel, and a nitrogen inlet is added dropwise 2-(2-bromoethyl) -1,3-dioxolane (4.7 g, 26 mmol) in 40 mL of tetrahydro- furan. The rate of addition is adjusted so as to maintain the reaction temperature below 50°C. The reaction is then allowed to stir for 1 hour at 25°C. 120 mL of tetrahydrofuran is mixed with potassium 3,4- dichlorobenzoate (5.0 g, 22 mmol) under a blanket of nitrogen. The Grignard solution is then quickly decanted away from the unreacted magnesium turnings, and added dropwise to the rapidly stirring potassium benzoate suspension. The reaction is then allowed to

. : Lo pr . - . Cpe pe -— 61 -— stir for 24 hours at 25°C. Fifty mL of diethyl ether - and 15 mL of 3N hydrochloric acid are added to the reaction mixture and the layers separated. The organic layer is washed with saturated aqueous sodium bicarbon- ate until neutral followed by one washing with 10 mL of brine. Drying over sodium sulfate, and rotary evapora- tion yields a beige semisolid which is chromatographed over silica gel using 3:1 hexane-ethyl acetate as eluent to give the keto-acetal (4.3 4g, 60%) as a white solid, m.p. 115-117°cC.

EXAMPLE 28

Preparation of 3-(3,4-dichlorobenzoyl) propionaldehyde i

I c 1 "] HO,C-COH C1 0 Ha0/ETOH/ CHO

C1 C1 ’s Ten grams (26 mmol) of 3',4'-dichloro-3-(1,3~- dioxolan-2-yl)-propiophenone is added to 30 mL of 0.2M oxalic acid (made by dissolving 0.9 gd of oxalic acid dihydrate in 30 mL of water) and 5 mL of ethanol. The mixture is refluxed for 1 hour and then allowed to 3 cool. Most of the ethanol is rotary evaporated off and 0 . 100 mL of diethyl ether is added along with 20 mL of saturated aqueous sodium bicarbonate. The layers are ] separated and the organic phase is dried over magnesium sulfate. Rotary evaporation yields a viscous yellow meme “ TER 20180 -— 62 -— ’ 0il which is chromatographed over silica gel using 3:1 . hexane-ethyl acetate to give the keto-aldehyde (6.3 g, 75%) as a white solid.

EXAMPLE 29

Preparation of 2-(3,4-dichlorophenyl) pyrrole 0 c1 | NH, OAC c1 “I \

CHO ETOH

A N ci H C1

To a suspension of 3-(3,4-dichlorobenzoyl) propionaldehyde (6 g, 26 mmol) in 60 mL of absolute ethanol is added ammonium acetate (4 g, 52 mmol). The reaction is refluxed for 20 minutes and allowed to cool. Most of the ethanol is rotary evaporated and 200 nL of 1:1 dichloromethane-diethyl ether along with 50 mL of water is added. The layers are separated and the ’ organic phase is dried over sodium sulfate. Rotary 25 . . : evaporation yields a dark brown oil which is chromato- graphed over silica gel using 3:1 hexane-ethyl acetate as eluent to give the pyrrole (4.6 d, 83%) as a light brown solid, m.p. 49-51°cC.

A Ea - 63 -

EXAMPLE 30

Preparation of 5-(3,4-dichlorophenyl)pyrrole-2-carboxa- ldehyde

C1 C1

N 1) OMF/PcCi, N

H (1 ————— OHC H C1 2) Naofc

To 10 mL of dimethylformamide stirring under nitrogen in a 50 mL round bottom flask is added phos- phorus oxychloride (0.6 mL, 6.5 mmol) dropwise via syringe. The solution, warms and becomes light yellow in color. It is allowed to stir for 20 minutes before the portionwise addition of 2-(3,4-dichlorophenyl)pyr- role (1 g, 4.7 mmol). The beige suspension which results is allowed to stir for 30 minutes before being heated to 50°C for 40 minutes. A solution of sodium acetate (10 g, 122 mmol) in 15 mL of water is added to the cooled reaction which is then allowed to stir for . 20 minutes. A beige precipitate is filtered off from the reaction mixture and air-dried for 20 hours to give the essentially pure aldehyde (1.1 g, 95%), mp > 200°c.

IEE Co Co - _. SE CER hm TTI tn mee i eR es AT ila tke NALS ? . ar

CA ; -_— 64 —

EXAMPLE 31 "Preparation of 5-(3,4-dichlorophenyl rrole-2-carboni- trile

C1 ’ C1 / A HaN-050,4H /\

OHC N , NC N

H CL ETOH/H,0 f c1

To a suspension of 5-(3,4-dichlorophenyl)pyr- role-2-carboxaldehyde (1.5 g, 6.2 mmol) in 20 mL of water and 20 mL of ethanol, is added hydroxylamine-0- sulfonic acid (0.7 g, 6.2 mmol). The reaction is 20 . . . oe refluxed for 1 hour during which time a gray precipi- tate appears. After being allowed to cool, the reac- tion is filtered to give essentially pure nitrile (1.5 g, 99%) as a gray solid, m.p. 170-171°C.

Co Sas ®owe me Lo 4d Ce Cee , EE Sop RNG ERR

Ct Sr aT Fo c- vee Coa cfr dkny ARR enter mm et eA LL - : CL : CT Chri eT ST ee pn AL EER as -— 65 -—

EXAMPLE 32 ) " Preparation of 3,4-dibromo-5-(3,4~-dichlorophenyl r- role-2-carbonitrile

Br Br

C1 C1 1 /\ NBS /\ 0 NC N NTN

H H

C1 THF C1

To a solution of 5-(3,4-dichlorophenyl)pyr- role-2-carbonitrile (0.5 g, 2.1 mmol) in 20 mL of tetrahydrofuran under nitrogen is added portionwise

N-bromo-succinimide (0.8 g, 4.2 mmol). The reaction is stirred at 25°C for 30 minutes before the addition of 10 mL of water and 40 mL of diethyl ether. The layers are separated and the organic layer dried over sodium sulfate. Rotary evaporation is followed by chromato- graphy over silica gel using 3:1 hexane-ethyl acetate ’ as eluent to afford the dibromopyrrole (0.5 g, 60%) as a brown solid, m.p. > 250°C.

— R618 -— 66 —

EXAMPLE 33 © preparation of 4-phenylpyrrole-3-carbonitrile

CN 50, } : Saab oih

CH,

NC

N

H

To a mixture of 5.0 g (39 mmol) of cinnamoni- trile and 7.6 g (39 mmdl) of (p-tolylsulfonyl)methyl 15 . . . . isocyanide in 35 mL of DMSO and 65 mL of ether is added over a 20 minute period a suspension of 1.86 g of a 60% oil suspension of sodium hydride (1.11 g; 46 mmol) in 80 mL of ether. The reaction mixture is maintained under nitrogen for an hour and then diluted with ether 20 . . and water. The ether layer 1s separated, dried over magnesium sulfate, and concentrated in vacuo. The resulting oil is chromatographed on silica gel using 1:1 chloroform ethyl acetate to give 2.5 g of cream-colored solids. Recrystallization from ether- hexane affords 1.15 g, m.p. 123-125°¢C; NMR M86-1077. :

Lit.: Tet. Letters 5337 (1972): m.p. 128-129°C. :

EXAMPLE 34 preparation of 2,5-dichloro-4-phenylpyrrole=-3- 1 oo carbonitrile

NC NC

Lo | + S0,Cl, —

N ci N C1

H H

To a stirred mixture of 0.66 g (3.9 mmol) of 4-phenylpyrrole-3-carbonitrile in 20 nL of dry THF cooled to ¢°c with an ice-water bath is added from a syringe 0.66 mL (1.11 g; 8.2 mmol) of sulfuryl chloride over a 4 minute period. The mixture is maintained at 5-10°C for an additional 45 minutes and then stirred an additional 30 minutes with the ice bath removed. After the reaction mixture is poured into 80 mL of ethyl acetate and 40 mL of water, the organic phase is separated, washed with water, and dried over sodium sulfate. Filtration through a short column of silica gel, rinsing with ethyl acetate, and concentration of the combined filtrated in vacuo gives 0.95 g of dark solid. Recrystallization from chloroform gives 0.42 g of off-white crystals, m.p. 195-196°C (dec.) .

Anal. Calcd for C,,HgCLyN,: c, 55.72; H, 2.55; N, 11.82; C1, 29.91.

Found: C, 55.66; H, 2.65; N, 11.69; Cl, 29.97.

ra

Following the procedures of Examples 33 and . 34, the following analogs are prepared. For the synthesis of 2,6-dibromo-4-(p-chlorophenyl)pyrrole-3- carbonitrile, the procedure of Example 33 is followed using bromine in dioxane to replace sulfuryl chloride and tet.ahydrofuron.

R

NC

SN Jy

LY N X

H o

R X Y m.p. C 4-C1 Cl Cl 237-240 (dec.) 4-CH Cl Cl 103-206 3 o 4-C1 Br Br > 245 oo SEL : ane - 69 -

EXAMPLE 35

Ethyl 4-(p-chlorophenyl)-pyrrole-3-carboxylate

I oy TT Nak cy cl 0

Il PR —

H

To a mixture of 5.63 g of a 60% sodium hydride/oil suspension in 200 mL of dry ether under nitrogen is added from an additional funnel a mixture of 23.5 g (122 mmol) of ethyl p-chlorocinnamate and 19.4 g (122 mmol) of (p-tolylsulfonyl)methyl isocyanide in solution in 180 mL of ether and 80 mL of dimethyl- sul fonide. The addition time is about 20 minutes and results in gentle refluxing of the mixture. After another 10 minutes stirring, the mixture is diluted with 100 mL of water. The mixture is extracted four times with ether which is then dried over magnessium : sulfate followed by concentrated in vacuo. The resulting solid is recrystallized from ethylene dich- lorite to give 7.8 g of crystals, m.p. 137-138°C.

Anal. Calcd for C, 4H, ,C1NO,: Cc, 62.53; H, 4.81; N, 5.61; Cl, 14.23.

Found: C, 61.31, H, 5.12; N, 5.327 Cl, 14.57.

Concentration of the mother liquor for the crystallization leaves additional crude ester which is carried on to the saponification step.

. - . . , ; . . ad | \ “a LER (ime ee : reo ee eed . Cl J . CT re TE * » . Cj in N

ULV y ‘ - 70 -

EXAMPLE 36 . Preparation of 3-(p-chlorophenyl) -pyrrole

Cl ° cl fl l

S NN Hg0 H - ’ + NaOH ——»

H H ct

H

A mixture of 22.0 g of crude ethyl 4-(p- chlorophenyl)-pyrrole-3-carboxylate from the recrystal- lization mother liquor and the recrystallized product from the previous step is stirred at reflux with 150 mL of 10% aqueous sodium hydroxide for 2.5 hours. The mixture is cooled, extracted with ether, and acidified to give a precipitate which on collection and drying weighs 11.6 gq.

A mixture of 10.5 g of the acid in 100 mL of p—-ethanolamine is heated at reflux for three hours.

After cooling, the mixture is poured over 400 mL of ice . and the resulting mixture is extracted four times with chloroform. The chloroform solution, after drying over magnesium sulfate and treatment with activated char- coal, is concentrated in vacuo to leave a brown solid.

Chromatography on silica gel using 1:1 ethyl acetate hexane gives 4.0 g of a white solid, m.p. 117-118%¢.

CUT emit Be eT cede LIL LUNA EEG = 71 -

EXAMPLE 37 : Ereparation of 3-(p-chlorophenyl)-pyrrole-2-caboxal- dehyde 1 0 5° + (COC), + (CHy) NOH

H c1

H

To a mixture of 0.86 g (12 mmol) of dimethyl- formamide in 10 mL of ethylene dichloride maintained under nitrogen and cooled in an ice bath is added 1.49 g (12 mmol) of oxalyl chloride in 10 mL of ethylene dichloride over a period of 25 minutes. The ice bath is removed, the mixture is stirred an additional 15 minutes and recooled in an ice bath. To this mixture is added 1.5 gq (8.5 mmol) of 3-(p~chlorophenyl) -pyrrole ,s in 25 mL of ethylene dichloride over a 20 minute period. The ice bath is removed and after an additional 30 minutes of stirring, the mixture is poured into 50 mL of ice-water and 6 mL of 50% sodium hydroxide. The resulting mixture is extracted with 10 ether and with chloroform and the combined organic mixture is dried over magnesium sulfate and concentrat- ed in vacuo. Purification of the resulting solid by chromatography on silica gel using 1:1 ethyl acetate hexane gives 0.63 g of off-white solid which is used directly for conversion to 3-(p-chlorophenyl) ~-pyrrole- 2-carbonitrile.

i = - 72 - OT

EXAMPLE 38

Preparation of 3-(p-chlorophen 1) -pyrrole-2-carboni- trile

C1 Ci + H,NOSO,H —>

N CH=0 N

H H CN

A mixture of 0.63 g (3.1 mmol) of 3-(p-chlor-" 15 . . ophenyl) -pyrrole-2-carboxaldehyde in 10 mL of water 1s stirred and ice-cooled while 0.52 g (4.6 mmol) of hydroxylamine-O-sulfonic acid in 10 mL of water is slowly added. After the addition, the cooling bath is a0 removed and the mixture is heated for 25 minutes. On cooling, the resulting solid is collected and shown, by

NMR, to be a mixture of product and starting aldehyde.

This mixture is reacted in the same manner with an additional 0.49 g (4.2 mmol) of hydroxylamine-0-sulfon- * ag jc acid in a total of 30 mL of water. The mixture is heated at 60-70°C for 2 hours. The mixture is cooled and the resulting solids are collected and purified by chromatography or silica gel using 1:1 ethyl acetate hexane to give 0.40 g of pink solid, m.p. 114-115°C.

as : Ce wl EES be BE Ls AE oo ] \ . iE . Hr }

Ca ie hag a Shen om Lhe See di el ARR

Prien ons EE eel 0 Se SAE nA ogra ie 3 po tie me hd ee So aa eS ES

Vidco ten Toei en Cr le . - LY ~ 4. RECT Fh ri 6p PIES, LK SIL “ LTT ae a er J Co Cd fron Sl . . : Cn . Ge LL ETT AR TE HE ks - 73 - .

EXAMPLE 39 preparation of 4,5-Dibromo=3- -chlorophenyl) -pyrrole- 2-carbonitrile ci - C1

Br + Br, ——

NN cn Br™ NT ew

H H

To a mixture 0.40 g (2.0 mmol) of 3-(p-chlor- ophenylpyrrole)-2-carbonitrile in 25 mL of chloroform } is added 0.63 g (4.0 mmol) of bromine. After 20 minutes, the precipitate which forms is collected and recrystallized from ethyl acetate to give 0.21 g of pink crystals, m.p. > 250°C.

Anal. Calcd for c,,HgBr,CIN: c, 36.62; H, 1.39; Br, 44.38; Cl, 9.85; N, 7.77.

Found: CC, 36.92; H, 1.32; Br, 44.62; Cl, 9.88;

N, 7.50

: EXAMPLE 40

Preparation of Ethyl S5-bromo-4-(p-chlorophenyl rrole- 3-carboxylate

S

0

I .

C—o0CaHs

C1 Ng THF [) + r

H

0

Cl

I

8r N

Ethyl 4-(p-chlorophenyl)pyrrole-3-carboxylate (1.6 g., 0.0064 mmol) is dissolved in tetrahydrofuran (40 mL). N-bromosuccinimide (1.14 g., 0.0064 mmol) is added in small portions at 25-289C. After the addition is complete, the solution ig stirred overnight at room temperature. The solution is concentrated in vacuo and the solid residue partioned between water and ether.

The ether layer is separated and dried over magnesium sul fate. Work-up of the ether extract leaves 1.9 g (90%) of a white solid which is purified by stirring 10 with a mixture of 80/20 hexane/ethyl acetate. The insoluble solid (1.3 g, 62%) is collected and has m.p. 161-164°cC.

Calcd for C,4H,,BrCINO,: Cc, 47.50; H, 3.34; N, 4.26;

Br, 24.33; C1, 10.80.

= . emp - Beep Leen Co. . - : SE ELT no Co oo Tm - 75 —_

Found: C, 47.39; H, 3.38; N, 4.12; Br, 24.29; : Cl, 10.77 : | EXAMPLE 41

Preparation of 5-bromo-4-(p-chlorophenyl rrole-3- carboxylic acid

COO0C, Hg COOH

C1 C1 / \ + 1072 NaOH — /\

Br N Br N

Ethyl 5-bromo-4- (p-chlorophenyl)pyrrole-3- carboxylate (15 g., 0.045 mmol) is added to 200 mL of 10% sodium hydroxide and the slurry heated to reflux.

After everything appears to dissolve the mixture is refluxed an additional 40 minutes. The mixture is ’ cooled, filtered and the filtrate acidified. The white precipitate (8.0 g, 58%) js collected and dried. The solid has m.p. >205°C and an NMR (d,-DMSO) which showed a pyrrole proton at 7.52 (4). The mass spectrum is also consistent for a monobrominated compound.

[a te : ERR : . i TU oY 2 Es iad FLT Lh =X z - Co N lm LIE Pr - 76 - . -

EXAMPLE 42 " Preparation of 2-bromo-3-(p-chlorophenyl) pyrrole

COOH

C1 C1 /\ HoNCH,CH, OH /\ ————3

Br h Br N 5-bromo-4- (p-chlorophenyl) pyrrole-3-carboxy- lic acid (8.0 g., 0.026 mmol) is added to aminoethanol : (24 mL) and the slurry slowly warmed to 110-120°C and held at that temperature for 1 hour. The solution is cooled and poured into water and extracted with ether.

The ether extract, by thin layer chromatography (75/25, hexane/ethyl acetate), shows a major fast moving spot and a slower moving minor component. Work-up of the . ether leaves a dark solid (4.0 g., 56%) which is 2- bromo-3-(p-chlorophenyl) pyrrole and is used immediately to prepare 5-bromo-4-(p-chlorophenyl)pyrrole-2-carboni- ‘ trile.

CTT eet ver gl eres : to Le Te Cone : rl Ce iE eh oo Ce la oo LDR -_ 77 -_

EXAMPLE 43 ; Pre aration of S5-bromo-4-(p-chlorophenyl rrole-2- carbonitrile 1 13

TY CISOGNCO + oH —> ti BR ar N Br CN

A freshly prepared sample of 2-bromo-3-(p- chlorophenyl)pyrrole (4.0 g., 0.015 mmol) is dissolved in dry dimethoxyethane (25 mL). Then while holding the , temperature below 25°¢, chlorosulfonyl isocyanate (3.08 0 g., 0.022 mmol) is added. After stirring overnight, the solution is treated with dimethylformamide (6 mL) and stirred for 3 hours. Finally, the solution is poured into water precipitating a brown solid (3.8 4g, ’ 25 90%) . Dry column chromatography (80/20 hexane/ethyl acetate) yields 1.4 g (33%) of white solid with m.p. 202-204°C.

Calcd for C,,HgBICIN,: Cc, 46.90; H, 2.13; N, 9.95; C1, 12.61; Br, 28.39.

Found: CC, 47.20; H, 2.09; N, 9.80; C1, 12.36; Br, 27.42.

; 14 ae é 4 ¥ 3 5 5 - 78 - ~ 20180

EXAMPLE 44 - Preparation of 3,5-Dibromo-4-(p-chlorophenyl)pyrrole=2- carbonitrile i Br oxane c1 : + Br ER c1 & [ \) z Zs J §

CN N CN

Br H Br H

A sample of 5-bromo-4-(p-chlorophenyl) pyrrole -2-carbonitrile (2.2 g., 0.0078 mol) is dissolved in 30 mL of dry dioxane. The solution is heated with bromine (1.3 g., 0.008 mol) in dioxane (20 mL) and then stirred , . . . overnight at room temperature. The reaction mixture 1s poured into water precipitating a tan solid (2.6 g., 92%). A portion (1.6 g) is purified by flash chromato- graphy using 75/25 hexane/ethyl acetate to give 0.8 g

Ls of grey solid with m.p. 191-194°cC. .

Calcd for C,,HgBr,CIN,: c, 36.61; H, 1.38; N, 7.76; ci, 9.84; Br, 44.3.

Found: C, 37.46; H, 1.25; N, 7.41; C1, 9.53; Br, 42.99.

et ik “ Li Eg p Xe CRE vl ' mee . TE } tween dy -— 79 —

EXAMPLE 45 3 : » ! preparation of 3-(3,4-dichlorophenyl)-4-nitropyrrole ci NO, SO c1 CH,

C1

C1 02

N

H .

Sodium hydride (2.66 g of a 60% suspension in oil is rinsed with dry ether; 66 mmol) and suspended in 150 mL of dry ether. To this mixture is added over 15 minutes a mixture of 12.0 g (5.5 mmol) of 3,4-dichloro- g-nitrostyrene and 10.8 g (5.5 mmol) of (p-tolylsulfon- yl)methyl isocyanide in 50 mL of DMSO and 150 mL of ether. The mixture is stirred for 1.5 hours and then © diluted with 150-200 mL of water and additional ether.

The ether layer is separated, dried over magnesium sulfate, and concentrated in vacuo. The resulting 10.6 g of crude product is purified by chromatography on silica gel using a 4:1 mixture of chloroform and ethyl acetate. A 7.2 g solid fraction is recrystallized from chloroform-ethyl acetate-hexane to give 3.0 g of yellow solid, m.p. 187-188°C (dec.) .

Anal. Calcd for C1oHeCLoN,0,¢ c, 46.72; H, 2.35: N, 10.90.

Found: C, 46.96; H, 2.60; N, 9.77

CT ye . Se Sa .er we i EE , . i ein } . } Co . CO . is ry ee . - Creel - - El or Re

EE OER UE oo Eom LT ome

PR : » J - 80 - . ) A

EXAMPLE 46 , Preparation of 2,5-Dichloro-3-(3,4-dichlorophenyl) -4= : " nitropyrrole ci C1 0,N 0O,N 2 c1 2 c1

Lo +80,C1,—>

N c1 N c1

H : H

To a mixture of 3-(3,4-dichlorophenyl)-4-ni- 15 . tropyrrole (2.5 4g, 9.7 mmol) warmed to about 40% in 200 mL of chloroform is added over one minute 2.95 ¢ (22 mmol) of sulfuryl chloride. After another hour, the mixture is diluted with 100 mL of saturated sodium bicarbonate solution and 300 mL of ether. The organic layer is separated and dried over magnesium sulfate.

Concentration, in vacuo, leaves a brown solid which is chromatographed on silica gel using 4:1 chloroform ethyl acetate. An orange solid fraction is recrystal- . 25 lized from chloroform and then rechromagraphed on silica gel using 4:1 chloroform ethyl acetate to yield 0.36 g of yellow solid, m.p. 193-194°C.

Also prepared by procedure of Examples 45 and 46 above is 2,5-dichloro-3-nitro-4-phenylpyrrole, m.p. o 193-194 C(dec.).

Fr J : o or ; oe EL Co - SEE ur 5 A or oe Sth ELE airidste

UU Ce Te CRE — 81 -—

EXAMPLE 47 , Pre aration of 5-(p-chlorophenyl)pyrrole-2,4-dicarbo- nitrile

CN

L DMF

N +C1S0,NCO+(CH3)pNCHO

H C1

CN

+ A

Ne

N

C1

A sample of 2-p-chlorophenyl-3-cyanopyrrole, prepared by the method of Example 4, (3.0 g, 0.015 mole) is dissolved in 50 mL of dry dimethoxyethane. To this solution is added chlorosulfonyl isocyanate (3.39 g, 0.024 mole). The addition is exothermic and some cooling is necessary. After stirring 3 hours at room temperature, dimethylformamide (6-7 mL) is added and the solution is stirred 4 hours more. The solution is then poured into water precipitating a white solid (3.4 g, 100%). A sample (1.0 g) is purified by dissolving in ethyl acetate and then passing the solution through a 60 mL course filter funnel packed with silica gel.

The filtrate is concentrated to yield 0.7 g of a white solid with m.p. 235-240°C.

Co - 82 -

Following the procedure of Example 47, the following analogs are prepared:

CN : — mi R

N

H

L

R L m.p. °° 3-C1 4-C1 >225°¢C

H 4-OCF, 185-190°C

H 4-CF, 180-185°C

EXAMPLE 48

Preparation of 3-Bromo-5- ~chlorophenyl rrole-2,4- dicarbonitrile ’

CN B CN

Dioxane A

NC \ +Br, —> Ie +

H c1 c1

: nL CT ey - Care } jo Ce emEse aye a REY - 83 -

A sample of 5-(p-chlorophenyl)pyrrole-2,4- ; dicarbonitrile (1.0 g, 0.004 mole) is dissolved in 20 " mL of dioxane and a solution of bromine (0.8 g, 0.005 mole) in dioxane (10 mL) is then added thereto. The solution is stirred several hours at room temperature and then poured into water precipitating a white solid (1.2 g, 100%). The solid has a m.p. >225°%C and a mass spectrum of a sample gives a pattern consistent with the desired structure.

Following the procedure set forth above in

Example 48, the following additional compounds are prepared: 13 Br / 2 CONC, Uy 23 R L m.p. oO 3-C1l 4-C1l >250°C

H 4-OCF , 218-223°C

H 4-CF, 239-241°C

» . . | : . . . . wy Se § Ca wy oy Apa a

Ce ae . SO hE » : . O UU - 84 -

EXAMPLE 49

Preparation of bromofumaronitrile

CN CN

= Bra/CHC13/ /\ < _—_————— —_—

NC (-HBr) NC Br

Under a nitrogen purge, fumaronitrile (15.6 g; 0.2 mol) in CHCl, (150 mL) is heated to reflux, resulting in a clear solution. A solution of bromine (5.3 mL; 0.2 mol) in CHCl, (25 mL) is added dropwise over 30 minutes, resulting in a slow decolorization and acidic (pH test paper) fumes being released. The solution is refluxed another 90 minutes, during which time most of the color has been discharged. The solution is cooled and solvent is removed under reduced pressure, leaving an amber oil (weight approximately © 25 theoretical for bromofumaronitrile). The oil is subjected to bulb-to-bulb distillation (0.2 mm Hg), maintaining the temperature pelow 120°C (above that point, a rapid decomposition of material occurs). A semi-solid is obtained which slowly forms a waxy, amber solid, m.p. - 43-47°C. calcd for C,HBIrN: Cc, 30.57; H, 0.64; N, 17.83.

Found: C, 29.13; H, 0.757 N, 16.94.

CL De RETR Be TU TO co : So ER FEE

Cn CoA eee : - CEE - 85 -—- ; EXAMPLE 50

Preparation of 2-phenyl-pyrrole-3,4-dicarbonitrile

CN NC

S

: — + T™S — J

NC Br N- «J

NC CN

HMPR/3 equiv.H,0

NH 9 2 (-TMS ,-HBr , CH SH)

Under a nitrogen purge, a solution ot bromo- fumaronitrile (4.7 g; 0.03 mol) and N-(trimethylsilyl) methyl-S-methyl-benzene-thioimidate (7.1 g; 0.03 mol) in hexamethylphosphoramide (HMPA) (35 mL) is stirred at room temperature. In a single portion, water (1.6 mL): 0.09 mol) is added, washed in with HMPA (10 mL). The solution almost immediately begins to exotherm, the temperature rapidly reaching 100°c before subsiding.

The resulting dark red solution is allowed to stir at ambient temperature 20 hours. Pouring the reaction mixture onto an ice/water mixture. results in a gummy material which slowly yields a discreet beige solid.

This material is collected by filtration and washed with cold water and dried on the filter. After further drying (vacuum oven; 60°C), the material is twice recrystallized from C,H,Cl, (DARCO treatment) to yield 35 . a white powder.

: i SLO U : - 86 -

Calcd for C,H, N53: Cc, 74.61; H, 3.63; N, 21.76.

Found: C, 74.45; H, 3.84; N, 21.61. : m.p. = 197-200°C.

EXAMPLE 51

Preparation of 2-bromo-5-phenylpyrrole-3,4-dicarbon- itrile

NC CN NC CN

Uy Br,/CHC1, ae

NF Br Nf

Under a nitrogen purge, 2-phenyl-pyrrole-3,4- dicarbonitrile (1.4 g; 0.0075 mol) is added to CHCl, (35 mL), much of the solid dissolving. A solution of bromine (0.4 mL; 0.008 mol) in CHCI , (5 mL) is added dropwise over 20 minutes. Initially the color is discharged rapidly, but as a new, gummy solid begins to 2g precipitate, the color remains. After stirring 30 minutes at ambient, the mixture is brought to reflux, resulting in a much more discreet solid. After reflux- ing 90 minutes, the reaction mixture is cooled and an aliquot is removed and analyzed (HPLC), showing ca. 60% 0 starting material still remaining. In a single portion fresh bromine (0.2 mL; 0.004 mol) is added, and reflux- ing continued another 45 minutes whereupon an aliquot shows 10% starting material remaining. Another fresh portion of bromine (0.2 mL: 0.004 mol) is added to the refluxing suspension and refluxing is continued

Rt ne a rnd Ba ed Ye Te ERE pana it ODER.

Cun Bn i SO - Co TEE a oe ade Rt ae Ce Lo . } ’ Sa 2 ! FLAY woh SRR another 30 minutes. The suspension is cooled and ! stirred 18 hours at room temperature. Solvent is removed under reduced pressure to yield a greenish solid which is extracted with hot CHC1,, leaving behind a dark residue. The extract is treated with DARCO and filtered hot. The clear yellow filtrate quickly began to deposit a white precipitate. After cooling to -10%%, the white solid is collected by filtration.

Calcd for Cy, HgBIN,:! C, 52.94; H, 2.21; N, 15.44; Br, 29.41.

Found: C, 51.64; H, 2.35; N, 14.91;

Br, 28.69. m.p. = 225-258°C.

EXAMPLE 52

Preparation of 2-(3,4-Dichlorophenyl)-5-nitropyrrole=3- carbonitrile

CN CN

7 \ + HNO; + Ac,0 —> /\

N N

H cl 02 H 7 Nei

Cl Cl i

Co oy oo . Ce

Ly

A

- 88 - , 2-(3,4-Dichlorophenyl)pyrrole-3-carbonitrile “(3.0 g, 0.013 mole) is added to acetic anhydride (50 mL) and 90% nitric acid (0.6 ml) with very little exotherm. The mixture is slowly warmed to 30° and is then held at 30-33° until everything goes into solu- tion. Gradually a new solid precipitates. The mixture js stirred for 2 to 3 hours at room temperature and then poured into water and ice to decompose the acetic anhydride. After stirring 1 hour the mixture is filtered and the solid (2.9 g, B82%) collected and dried. A portion (1.5 g) is purified by column chroma- tography on silica gel using 75/25 hexane/ethyl acetate for elution to give 0.7 g of yellow solid with m.p. 228-231°. calcd for C,H Cl, N;0,: c, 46.80; H, 1.77; N, 14.89: cl, 25.17

Found: C, 46.50: N, 1.96; N, 14.27: Cl, 24.30.

By the same procedure, starting with 2-(p- chlorophenyl)pyrrole-3-carbonitrile, 2- (p-chlorophenyl) - _5-nitropyrrole-3-carbonitrile is obtained, m.p. 201-206°C. Also, - (ptrifluoromethylphenyl) pyrrole-3- carbonitrile gives 2- (p-trifluoromethylphenyl)-5-nitro~ pyrrole-3-carbonitrile by the above procedure. This compound has a melting point of 164-165.5°C.

Ce eR TT eT 2 Co CTR

ChE TET a. igh

Comme Coe - ’ ' - CER Ee - : . whoa Ll arel , EXAMPLE 53

Preparation of 4-Bromo-2-(3,4-dichlorophenyl)-5-nitro- pyrrole-3-carbonitrile

Br

CN CN dioxane i \ + Brp —> / \ oN OW 0eN™ 2 H Cl

H Cl

Cl

Cl . 15 2-(3,4-Dichlorophenyl)-5-nitropyrrole-3-carb- onitrile (0.5 g, 0.0017 mol) is dissolved in dry dioxane (10 mL). To this solution is added bromine (0.28 g, 0.0017 mole) in dioxane. After stirring overnight, the solution is poured into water precipita- ting a tan solid (0.54 g, 88%). Recrystallization from . acetonitrile (5 mL) gives 0.26 g of tan solid with m.p. 195-200°C.

Calcd for C,,H4BrCl,N,0,: Cc, 36.57; H, 1.10; N, 11.63;

Br, 22.13; Cl, 19.67.

Found: C, 36.46; H, 1.29; N, 11.50; Br, 21.63; Cl, 19.28.

Following the above procedure of Example 53, but starting with 2-(p-chlorophenyl)-5-nitropyrrole-3- carbonitrile gives 4-bromo-2- (p-chlorophenyl)-5-nitro- pyrrole-3-carbonitrile, m.p. 180-185°C. :

Sol ol ; Ce md To me DR

Co te I RE 26180 . * ’ : EXAMPLE 54 5-(3.4-Dichlorophenyl)-4-nitropyrrole-2-carbonitrile

NO,

C1 C1

JN no, J \

NC N —_— NC N

H c1 ACO c1

To a suspension of 5-(3,4-dichlorophenyl)pyr- role-2-carbonitrile (1.2 g, 5.1 mmol) in 25 mL of acetic anhydride at 30° under nitrogen, is added dropwise 90% nitric acid (0.3 mL, 5.1 mmol). The reaction exotherms to 45°C and becomes a green solu- tion. After being allowed to stir for 2 hours the reaction is poured into 50 mL of water and stirred vigorously for 5 minutes. The beige precipitate which . results is filtered off and dissolved in a minimum amount of acetone. Chromatography over silica gel using 3:1 hexane-ethyl acetate affords the nitropyrrole (1.2 g, 84%) as an off-white solid, m.p. >200°C. :

EXAMPLE 55 3-Bromo-5-(3,4-dichlorophenyl)-4-nitropyrrole-2-carbon- ; itrile

NO, Br, NO,

C1 C1 7 Ce, /\ 0)

To a suspension of 5-(3,4-dichlorophenyl)-4- nitropyrrole-2-carbonitrile (0.6 g, 2.1 mmol) in 10 mL of dioxane at 25°¢, under nitrogen, is added dropwise a solution of bromine (0.3 g, 2.1 mmol) in 5 mL of dio- xane. The reaction is allowed to stir overnight.

Addition of 50 mL of water causes precipitation of a yellow solid which is collected and vacuum oven dried (50 mm Hg, 45°¢) to afford the brominated pyrrole (0.7 g, 90%) as a light yellow solid, m.p. >200°c.

EXAMPLE 56 4- (p-chlorophenyl) -2- (trifluoromethyl-2-oxazolin=-5-one

In a single portion, trifluoroacetic anhy- dride, (1.7 mL; 0.012 mol) is added to powdered 2-(p- chlorophenyl)glycine (11.4 4g; 0.06 mol), causing an immediate exotherm to about 40°c, a yellow color forming on the surface of the solid. As the mixture is slowly heated to 70°¢, more of the solid dissolves to } an orange/amber oil. All the solid dissolved in approximately 2 hours, and heating is continued another

~ =b6180 : hour. Solvent is removed under reduced pressure on a rotary evaporator. Toluene is twice added and removed under reduced pressure, but the odor of trifluoroacetic acid is still evident. This yellow semi-solid (yield theoretical; purity > 90% by HPLC) is the above-identi- fied compound and is used in the next step without further purification.

EXAMPLE 57

Preparation of 2- (p-chlorophenyl) -5- (trifluoromethyl) pyrrole-3-carbonitrile 4-(p-chlorophenyl)-2- (trifluoromethyl) -2-oxa- zolin-5-one (2.5 g: 0.01 mol) is dissolved in nitro- methane (50 mL). In a single portion, 2-chloroacrylo- nitrile (8.0 mL; 0.10 mol) is added to the solution, and the resulting solution is stirred 18 hours at reflux under a nitrogen ‘atmosphere. Cooling the red/brown solution to -5°c in an ice-acetone bath causes the formation of a precipitate which is collect- ed by filtration and washed with a small portion of cold nitromethane. The resulting tan solid is recrystallized from hot ethylene dichloride yielding } the product as white crystals (1.8 g; 56% theory), m.p. 238-241°C (dec.).

By utilizing the appropriate arylglycine in the procedure of Example 55 and following the procedure of this Example, the following 2-aryl-5-(trifluorometh- yl)pyrrole-3-carbonitrile were prepared:

CN

Gey

Cha N

L

R L n.p.%c : H H 215-218

H 4-CH, 191-193

H 4-OCH, 168-180 (dec. ) 3-Cl 4-C1l 245-246 (dec.)

H 4-CF, 218-219

EXAMPLE 58

Preparation of 4-Bromo-2-(p-chlorophenyl)-5-(trifluoro- methyl)pyrrole-3-carbonitrile

Under a nitrogen purge, a suspension or 2-(p- chlorophenyl) -5-(trifluoromethyl)pyrrole-3-carbonitrile (1.6 g; 0.005 mol) in acetic acid (25 mL) is heated, all the material dissolving to a clear solution at 15. about 60°C. A solution of bromine (0.8 mL; 0.015 mol) in acetic acid (10 mL) is added dropwise over 15 minutes to the refluxing solution. The solution is refluxed 6 hours then allowed to stir 18 hours at room temperature. The HPLC of the reaction mixture shows about 80% conversion to product. The mixture is heated back to reflux and more bromine (0.5 mL; 0.01 mol) in acetic acid (5 mL) is added dropwise. After refluxing another 3 hours, the aliquot chows > 95% conversion to . product. The reaction is cooled, and solvent removed under reduced pressure on a rotary evaporator to obtain a dark grey solid. Toluene is added to the mixture and removed under reduced pressure, but the odor of acetic acid still remains. The entire material is dissolved in hot toluene (75 mL) to a turbid solution which is treated with DARCO filter and filtered. The light pink solution deposits a white solid upon cooling to ambient. After cooling in the freezer, the solid is collected by filtration, washed with hexanes, and dried on the filter. Further drying in a vacuum oven at 45°C

TTT ee 4 - Co Con SLE hyd Eel ER . . : l -~ - 261g 130 —_ 94 —-— * provides the product (1.2 g; app. 60% theoretical): m.p. 247-250°C(dec.).

Anal. Calcd for C,HgBrClF,N,: C, 41.20; H, 1.43; N, 8.01; Br, 22.89; C1, 10.16; F, 16.31.

Found: CC, 41.27; H, 1.48; N, 8.10; Br, 22.92; Cl, 10.16; F, 16.03.

By brominating the appropriate 2-aryl-5-(tri- fluoromethyl)pyrrole-3-carbonitrile, obtained by the procedure of Example 57, according to the above recipe, the following additional examples are prepared:

Br N

C

/ -

L o

R L m.p. C ’ H H 235-238

H 4-CH 244-245 3 3-C1 4-C1 218-223

H 4-CF, 225-226

. I - - oor ged a - 95 -— , EXAMPLE 59 "Preparation of 2-(4-chloro henyl) -5-trifluoromethyl- pyrrole-3,4-dicarbonitrile 0

Han, 0 _ 2 OH N\ 0 r ="

N= B (CF,C0),0 sot —T cS N CH3NO,/ /18hr 72hr

Cl

Cl . N= =N

F

\ 1s IN

NH fF

Cl

Trifluorcacetic anhydride (3.1 mL: 0.022 mol) is added in a single portion to (4-chlorophenyl)glycine (2.0 g; 0.011 mol), causing an immediate yellow color and some refluxing. The mixture is slowly heated to ’ reflux, causing all the material to dissolve to a

Yellow/orange solution which is heated 2 hours further.

The reaction mixture is cooled, and solvent removed under reduced pressure. Toluene, is twice added and removed under reduced pressure to yield a very thick oil (Veo = 1800cm™ 1). This residue is dissolved (some insolubles) in CH, NO, (40 mL) and bromofumaronitrile (2.7 g: 0.018 mol) is added in a single portion. The resulting solution is heated at reflux 18 hours, yielding a dark red solution. Solvent is removed under reduced pressure and the dark residue is dissolved in

CH,C1,, some insolubles being removed by filtration.

: I : CTE hag - 96 -

The material is fractionated via dry column chromato- : graphy (silica gel; 3% 2-PrOH in CH,C1,), and appropri- ate fractions are taken. Evaporation of one fraction yields the desired compound as a yellow solid which is recrystallized from CH,CN (DARCO treatment) to yield a pale yellow solid (0.2 g). m.p. = 238-241°C. (some dec).

EXAMPLE 60

Insecticide and acaricide evaluations

All tests are preformed using "technical materials. All concentrations reported herein are in terms of active ingredient. All tests are kept at 27°C. :

Spodoptera eridania, 3rd instar larvae, southern . armyworm

A Sieva lima bean leaf expanded to 7-8 cm in length is dipped in the test suspension with agitation for 3 seconds and placed in a hood to dry. The leaf is then placed in a 100x10 mm petri dish containing a damp filter paper on the bottom and ten 3rd instar cater- pillars. The dish is maintained for 5 days before observations are made of mortality, reduced feeding, or any interference with normal moulting.

Spodoptera eridania, 7-day residual

The plants treated in the above Test are maintained under high intensity lamps in the greenhouse for 7 days. These lamps duplicate the effects of a bright sunny day in June in New Jersey and are kept on for 14 hour day length. After 7 days, the foliage is sampled and assayed as in the above-said Test.

Aphis fabae, mixed instar, bean aphid : Pots containing single nasturtium plants (Tropaeolum sp.) about 5 cm tall are infested with about 100-200 aphids one day before the test. Each pot is sprayed with the test formulation for 2 revolutions of a 4 rpm turntable in a hood, using a #154 DeVilbiss - atomizer. The spray tip is held about 15 cm from the plant and the spray directed so as to give complete coverage of the plants and the aphids. The sprayed pots are set on their sides on white enamel trays and held for 2 days, following which mortality estimates are made.

Tetranychus urticae(P-resistanté#strain),2-spotted spider mite

Sieva lima bean plants with primary leaves expaned to 7-8 cm are selected and cut back to one plant per pot. A small piece is cut from a leaf taken from the main colony and placed on each leaf of the test plants. This is done about 2 hours before treat- ment to allow the mites to move over to the test plant and to lay eggs. The size of the cut piece is varied to obtain about 100 mites per leaf. At the time of the treatment, the piece of leaf used to transfer the mites is removed and discarded. The mite-infested plants are dipped in the test formulation for 3 seconds with agitation and set in the hood to dry. Plants are kept for 2 days before estimates of adult kill are made using the first leaf. The second leaf is kept on the plant for another 5 days before observations are made of the kill of eggs and/or newly emerged nymphs.

Co ee i CS LRERE - 98 -

Diabrotic undecimpunctata howardi, 3rd instar southern * corn rootworm one cc of fine talc is placed in a 30 ml wide-mouth screw-top glass jar. One ml of the appro- priate acetone suspension is pepetted onto the talc so as to provide 1.25 and 0.25 mg of active ingredient per jar. The jars are set under a gentle air flow until the acetone is evaporated. The dried talc is loosened, 1 cc of millet seed is added to serve as food for the insects and 25 ml of moist soil is added to each jar.

The jar is capped and the contents thoroughly mixed on a Vortex Mixer. Following this, ten 3rd instar root- orms are added to each jar and the jars are loosely capped to allow air exchange for the larvae. The treatments are held for 6 days before mortality counts

Co are made. Missing larvae are presumed dead, since they decompose rapidly and can not be found. The concentra- tions used in this test correspond approximately to 50 and 10 kg/ha, respectively.

Rating Scale: 0 = no effect 5 = 56-65% kill ’ 1 = 10-25% kill 6 = 66-75% kill 2 = 26-35% kill 7 = 76-85% kill 3 = 36-45% kill 8 = 86-99% kill 4 = 46-55% kill 9 = 100% kill

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EXAMPLE 61 " Insecticidal evaluations

Heliothis virescens, 3rd instar tobacco budworm

Cotton cotyledons are dipped in the test formulation and allowed to dry in a hood. When dry, each is cut into quarters and ten sections placed individually in 30 ml plastic medicine cups containing a 5-7 mm long piece of damp dental wick. One third- instar caterpillar is added to each cup and a cardboard 1id placed on the cup. Treatments are maintained for 3 ’ days at before mortality counts and estimates of reduc- tion in feeding damage are made. 12 Empoasca abrupta, adults, western potato leafhopper

A Sieva lima bean leaf about 5 cm long is dipped in the test formulation for 3 seconds with agitation and placed in a hood to dry. The leaf is placed in a 100x10 mm petri dish containing a moist filter paper on the bottom. About 10 adult leafhoppers are added to each dish and the treatments are kept for 3 days before mortality counts are made. ) ,5 Blattella germanica, bait test, adult male German cockroach

A 0.1% bait is prepared by pipetting 1 nl of a 1000 ppm solution of the test compound in acetone onto 1 gram of cornmeal in a 30 ml wide-mouth bottle. 10 The bait is dried by passing a gentle stream of air into the bottle. The bait is placed in a 1 pint wide-mouth Mason jar and ten adult male cockroaches are added. A screen lid is placed on the jar and a small piece of cotton soaked in 10% honey is put on the top 3s of the screen lid. Mortality counts are made after 3 days.

, Blattela 'germanica, residue test, adult male German cockroach

One ml of a 1000 ppm acetone solution of the test material is pipetted slowly over the bottom of a 150 x 15 mm petri dish so as to give as uniform coverage as possible. After the deposit has dried, 10 adult male cockroaches are placed in each dish and the 1id is added. Mortality counts are made after 3 days.

Spodoptera eridania, systemic uptake, 3rd instar larvae, southern armyworm

The compound is formulated as an emulsion containing 0.1 gm of the test material, 0.2 gm of

Emulphor EL-620%® emulsifier, 10 ml of acetone and 90 ml of water. This is diluted 10-fold with water to give a 100 ppm emulsion for the test. Subsequent 10-fold dilutions are made with water as needed. Sieva lima bean plants, with the primary leaves expanded to a length of 7-8 cm, are cut off at least 3 cm above the soil level to avoid contamination with soil bacteria that will cause decay of the stem during the test. The cut stems are placed in the test emulsions and each stem is wrapped with a bit of cotton to hold the stem ) off the bottom of the bottle and to limit evaporation 23 and volatilization of the compound. The test is maintained for 3 days at 27°C to allow the compounds to be taken up into the plant. Following this, one leaf is removed from the plant and placed in a 100 x 10 mm petri dish with 10 southern armyworms as described in

Test III. Mortality counts and observations of feeding damage are made 3 and 5 days later.

Empoasca abrupta, Adults, Western Potato Leafhoppers,

Systemic Uptake

The compound is formulated as an emulsion 33 containing 0.1 gm of the test material, 0.2 gm of

Emulphor EL-620® emulsifier, 10 ml of acetone and 90 ml of water. This is diluted 10-fold with water to give a * 100 ppm emulsion for the test. Subsequent 10-fold dilutions are made with water as needed. Sieva lima bean plants, with the primary leaves expanded to a length of 7-8 cm, are cut off at least 3 cm above the soil level to avoid contamination with soil bacteria that will cause decay of the stem during the test. The cut stems are placed in the test emulsions and each stem is wrapped with a bit of cotton to hold the stem off the bottom of the bottle and to limit evaporation and volatilization of the compound. The test is maintained for 3 days at 27°C to allow the compounds to be taken up into the plant. Following this, one leaf is removed from the plant and placed in a 100 x 10 mm petri dish and tested as in Test VIII, above.

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EXAMPLE 62

A) Evaluation of test compounds as nematicidal agents ! Culture Maintenance: Cultures of C. elegans (Bristol strain from J. Lewis) are maintained on E. coli lawns on

NG Agar Plates at 20°C. New cultures are established weekly.

Nematodes for testing are washed from 4-5 day old cultures using Fresh Ascaris Ringers Solution (FARS). The worms are further washed with FARS, con- taining gentamycin, to reduce bacterial contamination and centrifuged to separate worms from wash solution.

This procedure is repeated three times. The washed worms are then added to C. briggsae Maintenance Medium (CbMM), from GIBCOa to which is added gentamycin (600 units/ml) and mycostatin (0.5 mg/ml).

The tests are then made with mixtures of three compounds, piggy-backed from another high capacity screening program to reduce additional labor and com- pound expenditures.

Compounds are dissolved in acetone and made up to volume with equal parts of water. The final test concentration of each compound in the mixture is 150 : ppm. The test material is micropipetted (25 ul) into a single well of a 96-well sterile tissue culture plate 28 (COSTAR)? and the solvent allowed to evaporate. These "treated" plates are used immediately or stored in a freezer without apparent adverse effects on the com- pounds.

A freshly prepared volume (50 ug) of C. elegans in CbMM is micropipetted into each treated well and several control wells per plate. Culture plate are incubated at 20°c.

Observations for efficacy are made under a . dissecting microscope at 4, 24 and 48 hours post-immer- sion. Immediately prior to reading the plate, it is

: gently tapped to stimulate the movement of the worms.

Activity is judged subjectively, but semi-quantitative- ly, based on the drug effects on motility of the adults and larvae. The criteria are as follows: 8 = no motility, 7 = markedly reduced motility in approximately 95% of worms, 6 = reduced motility, 5 = slightly reduced motility, 0 = normal motility, same as controls. Other factors indicating activity are easily noted such as death, rigor mortis, contraction, coiling, paralysis, abnormal twitching, reduced worm population in 48 hours and other deviation from normal behavior.

PROCEDURE FOR CAENORHABDITIS ELEGANS ASSAY

: 15 Day O .Inoculate E. Coli-NG Agar Dish With 30-50 C.

Elegans .Incubate At 20°c.

Day 4 .Harvest New C. Elegans Population .Wash With Antibiotics 20 .Transfer To CbMM .Add C. Elegans (25-100 UL) To "Medicated" wells? . .Observe For Activity At 4 Hours Post-

Immersion

Day 5 .Observe For Activity

Day 6 .Observe For Activity 2 Medicated Wells May Be Prepared Fresh Or Earlier And

Stores In Freezer

Data obtained in these tests are reported in

Table III below. 3s

LL | Cubes - 123 - ’ B) Root-Knot Nematode Assay

Populations of the root-knot nematode (Meloidogyne incognita) are maintained on Fireball tomatoes in the greenhouse. Egg masses are removed from the infested root surfaces and are kept on moistened filter paper for 24 hours to allow them to hatch.

Larvae emerge and drop into the water beneath the paper.

Larvae for test are transferred to cell plate wells containing test compounds at 300 ppm in 3% acetone, about 10 larvae per cell well. Infested wells are held at 27°C and mortality is determined 24 hours after treatment.

Data obtained are reported in Table III below.

- - Bis. 7

CTA

: Ce a AYER } ee lL oo oe ; COE AER - 124 - ) Table III

C. Ele. Root Knot 150 ppm Nematodes.

L A -300 ppm 4,5-dichloro-2-[p- - - 4 (trifluoromzthoxy)phenyl- pyrrole-3-carbonitrile 4,5-dichloro-2-(alpha, 9 9 5 alpha,alpha-trifluoro- p-tolyl) pyrrole-3- : carbonitrile 4,5-dibromo-2- (alpha, 9 9 0 alpha, alpha-trifluoro- p-tolyl) pyrrole-3- carbonitrile 2,3-dichloro-4-nitro-5- 0 0 9 phenylpyrrole 2,3-dichloro-5-(p-chloro- 9 9 9 phenyl) -4-nitropyrrole 2,3-dichloro~-5-~(3,4- 9 9 0 dichlorophenyl) -4- nitropyrrole _ 2-(p-bromophenyl)-4,5 9 9 6 dichloro-3-nitropyrrole 2,3-dichloro-4-nitro-5- 9 9 - (alpha,alpha,alpha- trifluoro-p-tolyl)pyrrole

Ce SE

Le Lo HA . ‘ Te 7 - t ~ - 125 ~-

EXAMPLE 63

Following the procedures of Examples 59 and 60, compounds of the invention are evaluated against a variety of insect species including: leaf hoppers, tobacco budworm, southern armyworm, and the German cockroach. The rating system is the same system used in the above-said examples. Data obtained are reported in

Table IV below. Where two or more tests have been . 10 conducted with the same test compound, the results are overaged. also, a - in the table indicates no test.

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Claims (1)

1. - . Co ! ¥ 8 3 Li , RCV BY:SYCIP LW OFFICES MLA, 5 5- 3-81 i 0:44 42088212071 —e} Nomad i] ) Co £ vo dessin committed. 1 w ot ate ’ / 3 5 Tu . } + oe / - Cl : ’ ° . 3 A a } . + ’ / } i i

   7. i » : r™ Pht y; ol ; oo] A Co a oft y _ ? ji 26 80 Me? pri f 00 . To Bos [ ' CLAIMS: bo - NE

   1. A process for the preparation of an. Co «=[2,2-di(¢,-C alkoxy) ethylanino]~g-cyanostyrene or MEL. «-[2,2-di(C,-C alkoxy) ethylamino]=g-nitrostyrene Ce : ~ represented by the structure: : : L Co Ce M W ( ’ // : R N-CHaCH(OC,-C4al kyl), i H : 1 wherein W is CN or NO, ; L is H, F, Cl, or Br; M and R are each independently H, C,=C alkyl, { , 4 ¢, C, alkoxy, c, Cjalkylthio, © Cqalkylsulf EL inyl, C,-C¢jalkylsulfonyl, cyano, I, ¢., Br, 4 I, nitro, cr, R,CF,2Z, R, CO, or NR,R, and ] when on adjacent positions and Luiken together . with the carbon atoms to which they are FE a = attached M and R may form a ring in which MR # 0 represent the structure: LE Bo, SS -0CH0-, -0CF,0- or ; 4 “ a 7 ’ Co kD Z 1; §(0) , or 0; : 7? is H, F, CHF,, CHFCl, or CF; - \ry/9 - > . X R, is H or €;-C,alkyl; ] . R, is H, C,-C,alky?, or ReCO: ol : Rg is H or Cy=Cyalkyl and ~ "BAD ORIGINAL n is an integer of 0, 1 or 2 : ch ; which comprises reacting a benzoylacctonitrile or / u-nitroacetophenone Co 4 the struc.ure:

   RCV BY:SYCIP LAW OFFICES MLA. 3 5= 3-81 Uidh 2033¢212911= vigienes 4 ¢ aR n——... Te Ri oor er DOSER 300 Xe ge te te Aes rn st to.

   L " \ R wherein L, M, R, and W are as described above with 2,2-di(c,-C alkoxy)ethylamine in the presence of an aromatic solvent at an elevated temperature.

   Noor : T AD ORIGINAL a + ’ . . ! 15628 3 RCV BY:SYCIP Lj Ot LCES MLA 3 5= 3-91 : 0:44 2033212811 414 rere ————— EE EEE EE SE—E————————— 1 Tae), « chp : ’ : ep. : Oo rest So as 0 Tipe, A of | A 0 LO EY Yap fl . 00 i I LTT CTE CLAIMS: ! : Wiad gt a . : — Pit]

   1. A process for the preparation of an aml 2, di(C,-C,alkoxy)ethylanino]~g-cyanostyrene or =. - a-[2,2-di(C,-C alkoxy)ethylanino]-5-nitrostyrene MH represented by the st_ucture: L H wherein W is CN or NO, : L is H, F, Cl, or Br; M and R are each independently H, C,-Cjaliyl, Cc, - oxy, C.o-Coalky in, Co-CLalvrlsuil- 1 Cyalk xy, C; Cjalkylth | Che uif inyl, C,-Cyalkylsulfonyl, Jyane, 4 Lt oF cE. 7 GC : AT I, nitro, C gr R, F.7, R,CO, or NR, . when on adjacent pesitions and Coen, with the carbon atoms to whion they « « attached M and R may foro a ving doowhoo ade y rec-resesl. the structure: “00H 0, -CClF,0- 3

   “~. oo ~~ > 5(0), or 0;

   ©. don, F, CHE, CHFCL, or CF

   R., ie CC ~Coallwyl, ©. Voiay, ov Wi ; pRB RTA Cy rCgathnay or LigR R, 1s H or Cp -Cya. kyl; 2, ie wm “CT. alkyl, To Bl, MET <, 40 kyl, or Re 3 Rg Lou or Cymiiyaakyl and AD ORIGINAL nis asin. Fo, 1 cr 2 TT WACh comprises po benvoyLs Lr trile or / ~nitroaceton eT Lhe oo Lit, /

   RCV BY:SYCIP LAW OFFICES MLA. 6- 3-91 ; 0:45 2033212971» 1410028 4 * a ¥ ~ han o A tether tt eaten ———— ee cals atm.

   L " I R wherein L, M, R, and W are as described above with 2,2-di(c,-C, alkoxy) ethylamine in the presence of an aromatic solvent at an elevated temperature.