CA1273345A - Process for the production of 3-phenyl-4- cyanopyrroles - Google Patents

Abstract

abstract A process for the production of a compound having the formula:

which comprises the reaction of a compound having the formula:

with a compound having the formula wherein X is the same or different substituent(s) selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalky, C1-6 alkylamino, C1-6 alkoxy, nitro, cyano and methylenedioxy;
COOR1 is a carboxylic acid or ester group, R2 is a C3-10 cyclic hydrocarbon group which may be substituted by substituent(s) which do not have adverse effects on the reaction;
n is 0, 1 or 2.

Description

S P E c I F I C A T I O N

P~OCESS FOR T~IE P~ODUCTION O~ 3-PIIENYL-4-CYANOPYRROLL~

The present invention relates to a novel process for the production of 3-phenyl-4-cyanopyrroles which are useful as intermediates for medically active compounds and agriculturally and horticulturally actlve compounds.
The above-mentioned pyrrole derivates are acylated, for example, at the l-position to obtain compounds useful as agricultural and horticultural fungicides described in Jpn. Kokai Tokyo Koho JP 81079672, JP 80051066, JP
80057508 and others.
A process for the production of 3-phenyl-4-cyanopyrrole is disclosed in Tetrahedron Letters No. 52, 5337-5340 (197Z) as below.

CH=CHCN ~ CH3 ~so2cH2Nc (Iv1 ~ base > ~ ~ ~CN

(I') However, under this process, the yield is as low as about 35Z, because complicated purifying processes are needed to obtain compound (I'). ~urther, the starting material (IV~ is undesirable as an industrial material in vie~ of the fact that the compound is manufactured through decarboxylation of alpha-cyanocinnamic acids or esters thereof, the conditions of ~hich manufacture are rigorous and the purification processes of the reaction mixture to obtain compound (IV) therefrom are complicated and require vacuum distillation or recrystallization, so that the yield of compound (IV) is very low. Thus, these processes are undesirable as commercial processes.

The present invention relates to a process for the production of a * ~'~

compound ha~lng the formula:

Xn ~ CN (I) uhich comprises the reaction of a compound having the formula:

Xn ~ -C~l=C~cooRl (II) with a compound having the formula:

R S02CH2NC (I~I) wherein X is the same or different substituent(s) selected from ~he group consisting of halogen, Cl_6 alkyl, Cl_6 haloalkyl, Cl_6 alkylamino, Cl_6 alkoxy, nitro, cyano and methylenedioxy;
COORl is a carboxylic acid or ester group;
R2 is a C3_10 cyclic hydrocarbon group which may be substituted by substituent(s) which do not adversely affect the reaction;
n is 0, 1 or 2, in an organic solvent in the presence of base(s).
As becomes clear from the reaction mechanism of the process of the present invention described later, each COORl radical in compounds (II) and R2S02 radical in compound (III) participates only at the intermediate stages of this reaction and is finally eliminated without any formation of residue(s) in the compound (I). Therefore, Rl and R2 may be anything which does not adversely affect..said reaction.
As Rl, hydrogen or a Cl_lo hydrocarbon group uhich may be substituted by substituent(s) not adversely affecting the reaction is desirably used; and as R2 a C3_10 cyclic hydrocarbon group uhich may be substituted by ', substituent(s) not adversely affecting the reaction is desirably used.

- The substituent(s) adversely affecting the reaction are ~ubstituent(s) reactive to the -N C of compound (III) and/or Xn oE coMpound I and II, for example, isocyanato, isothiocyanato, amino, imino, mercapto and hydroxy radicals. The other substituent(s) adversely affecting the reaction are the substituents which sterically hinder the reaction. In other words, large and rigid substituents block the contact of the reactants at the reaction point(s). Accordingly, those radicals are excluded from the desirable substituents used as Rl and R2-As the base(s), it is possible to use organic or inorganic bases such as sodium hydride, sodium alkoxide, potassium alkoxide, metallic sodium, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or the like.
As the organic solvent, it is possible to use ben~ene, toluene, ether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, dimethoxyethane or other aprotic solvent, when as the base(s), sodium hydride, sodium alkoxide, potassium alkoxide, or metallic sodium, is used, and dimethoxyethare is the ~`
best solvent in this case. In addition to the above specified orgznic solvents, it is also possible to use a lo~er alkyl alcohol, or a m-~ed solvent which is a mixture of a lo~er alkyl alcohol with a halogen-containing solvent, if as the base(s), sodium hydroxide, potassium hydroxide, potassium carbonate, or sodium carbonate is used. As the lower alkyl alcohol, methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, t-butanol etc. are included, and as the halogen-containing solvent, methylene dichloride, chloroform, carbontetrachloride, trichloroethane etc. are included.
The reaction temperature varies ~ith a combination of the raw materials, the kind of the base, and the solvents used, but normally it ranges between -30C and 100C, but a range of -10C to 40C may be more desirably used.
In the present invention, the reaction proceeds under mild conditions through the presumed reaction mechanisms as shown below, which are entirely different from those of the kno~n manufacturing methods.
! ``-`

Xn~CH=C" cOORl +R2S02CH2NC _B~Y- >

- Xn -,CN ~ CH Cl`COORl ¦

R -S~2 I R -S2 H
H

Xn -R2S02B ~11 Cl--COOR~
H~ ~ N~ ~ H

Xn "` +H20 ~ ~ -C _ C-CN ~ C02~RlOH

H

wherein B is base cation, Y is counter anion to B .
The following Examples illustrate the invention, but the invention should not be limited by those examples.

Example 1 :

CH C' CN + CH ~ - S02CH2NC

NaH ~ ~ ~ CN

s 10.06 g (50.0 m mol) Or alpha-cyanocinnamic acid ~thyl cs~er and 10.25 g (52.5 m mol) of tosyl methylisocyanide wcre dissolved ln a 80 ml solution of dried dimethoxyethane (hereunder often shortened to DME). The solution obtained was then fed dropwise, in a stream of N2 gas at a temperature ranging from 0 C to 5 C, into a 50 ml suspension of dried dimethoXyethane and 2.88 g (60.0 m mol) of 50% NaH to allow reactions to proceed.
After the dropwise addition was complete, the mixed liquid was stirred for one hour at room temperature to complete the reaction. Then, to the reaction mixture 50 ml of water ~as added and the mixture neutralized by lOZ
~Cl to pH 8. From the neutrali~ed mixture, dimethoxyethane was distilled off under reduced pressure, then 100 ml of water was added thereto, and the mixture was stirred for 30 min. to precipitate crystals. The crystals were filtered off and washed with water and toluene and dried. As the result 7.~8 g of 3-phenyl-4-cyanopyrrole was obtained. Yield 88.9Z, melting point 129-130C.

Example 2 :

Cl ~CI~=C COOCz~5 ~502Cii2~1C

C2NsC~ C~2C12 ~ ~ ~ CN

11.78 g (50.0 m mol) of alpha-cyano-0-chlorocinnamic zcid ethyl ester was dissolved in 80 ml of ethanol. The solution obtained wzs then cooled at a temperature 0 C to 3 C~before 4.o8 g ~60.0 m mol) of sodium ethoxide was added to it. After this, the solution was fed drop~ise at a temperature from 0C to 3C to a solution obtained by dissolving 10.25 g (52.5 m mol) of tosyl methylisocyanide in 70 ml of methylene chloride and the reaction ~as allowed 5 ;~ to proceed, with stirring, for one hour in the same temperature range, before it ~as complete. Then, to the reaction mixture 50 ml of water was added and the mixture neutralized to pH 8 by using 10~ HCl. From the ; neutr~ ed Mixture, methylene chloride and ethanol were distilled out under - reduced pressure, then lOo ~1 of water was added thereto, and the mixture was stirred ror 30 min. to precipitate crystals. ~h~ crystals i~ere filtered out and washed with water and dried. As the result, 9.93 g of 3-(2-chlorophenyl)-4-cyanopyrrole was obtained. Yield 98.o%1 melting point 138-139-C.

Example 3 :
C~30 C~30 ~ CH=C ~ COOH ~ CH3 ~ _ S02CH2NC

DME CH30 - ~ \} ~ ~ C~
N

12.62 g (225.0 m mol) of potassium hydroxide was added to lOo ml of dimethoxyethane. The solution was then cooled at a temperature from 0 C to 10C, 11.66 g (50.0 m mol) of alpha-cyano-3,4-dimethoxycinnamic acid was added thereto, and the mixture stirred for 30 min. at the same temperature. The liquid was then fed dropwise over one hour, at room temperature, to a solution of 10.25 g (52.5 m mol) of tosyl methylisocyanide in 60 ml of dimethoxyethane. ~hen the drop~ise addition was ended, the mixed liquid was stirred for t~o hours at room temperature till the reaction was complete.
Then, to the reaction mixture 70 ml of water was added and the mixture neutralized to pH 8 by 10~ HCl. From the neutrali~ed mixture, dimethoxyethane was distilled off under reduced pressure, then 80 ml of water was added-thereto, and the mixture stirred for 30 min. to precipitate crystals. The crystals were then filtered off and uashed with water and dried. As the result, lO.S0 g of 3-(3,4-dimethoxyphenyl)-4-cyanopyrrole was obtained. Yield 92.0~, Nelting point 212-214C.

- ~ Example 4 : J~ 7;~

NC~ CH=C~ COOH ~ C113 ~S02CH2NC

K2CO ~ ~ NC--~3 CN
CH30H, CH2C12 ~

20.73 g (150.0 m mol) of potassium carbonate and 9.91 g (50.0 m mol) of alpha-cyano-p-cyanocinnamic acid were added to 80 ml of methanol and stirred for 30 min at room temperature. The reaction liquid was then fed dropwise, at a temperature ranging between 30C and 40C, to a solution of 10.25 g (52.5 m mol) of tosyl methylisocyanide in 70 ml of methylene chloride. After the dropwise addition ended, the reaction mixture was stirred for three hours at 40C to complete the reaction. Then, to the reaction mixture 50 ml of water was added and the mixture was neutralized to pH 8 by lOZ HCl. From the neutralized mixture, methylene chloride and methanol were distilled off under reduced pressure, then, 100 ml of water was added thereto, and the mixture i `
stirred for 30 min. to precipitate crystals. The crystals were filtered off and washed with water and dried. As the result, 7.83 g of 3-(4-cyanophenyl)-4-cyanopyrrole was obtained. Yield 81.05Z, melting point 170-172C.

Example 5 :

Cl Cl CH=C~ COOH t CH3 ~ 502CH2NC

Cl Cl CH3OH, CH2Cl2 ~ ~ N ~

12.62 g (225.0 m mol) of potassium hydroxide was dissolved in 80 ml of methanol. While being cooled at a temperature 0 to 10C, 8 ~-~7 ~
~~" 12.10 g ~50.0 m mol) of alpha cyano-2,3-dichloroclnnamic acid were added and the mixture stirred for 20 min. ln the same temperature range. A
solution of 10.25 g (52.5 m mol) Or tosyl methylisocyanide in 70 ml Or methylene chloride was added dropwise, at a temperature rrom 0 to 5 C, to the above mixture. The reaction mixture was then stirred for 30 min. at the same temperature to complete the reaction. Then, to the reaction mixture 50 ml of uater was added and the mixture neutralized to pH 8 by lOX HCl. From the neutralized mixture, methylene chlorlde and methanol were distilled off under reduced pressure, then, 100 ml of water ~as added and the mixture was stirred for 30 min. to precipitate crystals. The crystals uere filtered off and uashed with water and dried. 11.73 g of 3-(2,3-dichlorophenyl)-4-cyanopyrrole uas obtained. Yield 99.0Z, Melting point 152-153C.

Example 6-18:
~,~
"`~ Reactions were carried out in the same manner as Example 5. Table 1 shous the result.

.~

9 ~ 5~

Table 1 example material compound product compound .
~'`C"'~
7 CH=C~cooH g~CN 9 4.0 I L ~ 1 l 9 ~/~ CH=C~CooH ~N,D~

9 1~)~ CH = C ~CN O ~CN 9 2.1 1 9 1 ~ 1 9 3 NO 2 ~NO 2 I o ~CH C~cOOH lH~ 89. 2 I I ~~1 1 3 . _ 1 1 ~N~CH=c\cooH CH ~N~CN 9 2.3 14 2~1 5 0 1 2 ~CH=C~ CN ~ CN 9 7.8 1 1 6~1 1 7 1 3 CH3~CH=C~ CH3~--CN 8 5 7 i :L() example material compound product compound _ ~eld m~ ng . t%) point C) 1 4 CC~ CH = C ~ COOH C~CN 9 O. 1 1 4 9 ~ 1 5 0 C~
1 5 ~CH c\cooH ~[~CN 9 3.0 1 4 5~1 4 7 B r 1 6 ~CH= C~ ~ CN 8 9 6 1 3 ~--1 3 3 1 7 ~ CH C~ CN H 8 7. 6 2 1 ~ ~ 2 2 2 ~6 L] ~J~ 3 Example 19 :

3 --COOH ~ S02C~12tlC

KOH ~ ~ ~ CN
CH30H. CH2Cl2 H

26.30 g (450 m mol as purity of 96S) of potassium hydroxide was dissolved in 200 ml of methanol. While being cooled at a temperature from 0 to 5C, 17.30 g (100 m mol) of alpha-cyanocinnamic acid were added for 60 min. into the solution with stirring in the same temperature range. To the stirred reaction mixture thus obtained at a temperature from 0C to 2C, a solution of 18.48 g (102 m mol) of phenylsulfonyl methylisocyanide in 180 ml of methylene chloride was added dropwise over 70 min. The reaction mixture was then stirred for 3 hours at the same temperature. ~hen, to the reaction mixture 200 ml of water was added and the mixture neutralized to pH 8 by 10%
HCl. From the neutralized mixture, methylene chloride and methanol ~ere distilled off under reduced pressure, then 200 ml of ~ater was added thereto, and the mixture stirred for 40 min. to precipitate crystals.
The crystals were filtered off and washed with water and dried. 12.65 g of 3-phenyl-4-cyanopyrrole was obtained. Yield 75.2%, melting point 129-130 C.

Example 20 :

CH=C ~ COOC2H5 ~ S02CH2NC

KOH ~ ~ CN
C2H50H, CH2C12 ~ ~ N~ -i 26.30 g (450 m mol as purity of 96~) of potassium hydroxide was dissolved in 200 ml of ethanol. While being cooled at a temperature ~rom -5C
to -3C, 20.10 g (100 m mol) of alpha-cyanocinnamic acid ethyl ester were added over 5 min. into the solution with stirring in the same ~emperature range. To the stirred reaction mixture thus obtained in the same temperature range, a solution of 18.48 g (102 m mol) of phenylsulfonyl methylisocyanide in 180 ml of methylene chloride was added dropwise for 60 min. The reaction mixture was then stirred for 2 hours at the -ame temperature to complete the reaction.
Thereafter, post-treatmen,s were conducted by similar methods as described in xample 19. 13.20 g of 3-phenyl-4-cyanopyrrole was obtained.
Yield 78.5%, Melting point 129-130 C

Example 21 : Cl CH=C~ COOH Cl S02CH2NC

CN

26.30 g (450 m mol as purity of 96Z) Or potassium hydroxide was dissolved in 200 ml of methanol. ~lhile being cooled at a temperaturc from 0C to 5C, ~0.76 g (100 m mol) of alpha-syano-0-chlorocinnamic acid were added for 60 min. into the solution with stirring in the same temperature range. To the stirred reaction mixture thus obtained in the same temperature range, a solution of 18.48 g (102 m mol) of phenylsulfonyl methylisocyanide in 200 ml of methylene chloride was added dropwise over 70 min. The reaction mixture was then stirred for 30 min. at the same temperature to complete the reaction.
Thereafter, post-treatments were conducted by similar methods as described in Example 19. 19.85 g of 3-(2-clllorophenyl)~ cyanopyrrole was obtained. Yield 98.0~, Melting point 138-139 C.

l3 ~ 3~3~
- . Example 22 :

CH=C~ COO~I ~ Cl ~ - S02Cfl2NC

CH30H, C~2Cl2 ~ ~ ~ - CN

26.30 g (450 m mol as purity Or 96Z) of potassium hydroxide was dissolved in 200 ml Or methanol. While being cooled at a temperature from 0C to 5C, 17.30 g (100 m mol) of alpha-cyano-cinnamic acid were added for 30 min. into the solution with stirring in the same temperature range. To the stirred reaction mixture thus obtained at the same temperature, a solution of 22.00 g (102 m mol) of 4-chlorophenylsulfonyl methylisocyanide in 220 ml of methylene chloride was added dropwise over 70 min. The reaction mixture was then stirred for 2 hours in the same temperature range to complete the reaction.
Thereafter, post-treatments ~ere conducted by similar methods as described in Example 19. 15.00 g of 3-phenyl-4-cyanopyrrole was obtained.
Yield dg.2~, Melting point 129-130 C.

Example 23 :
Cl ~ COOH ~ S02CH2NC

~OH ~ ~ CN
CH30H, CH2C12 ~ - i H

26.30 g (450 m mol as purity of 96Z) Or potassium hydroxide was dissolved in 200 ml of methanol. While being cooled at a temperature from 0C to 5C, 20.76 (100 m mol) of alpha-cyano-O-chlorocinnamic acid were added for 40 min. into the solution with stirring in the same temperature range.

3~
-~ To the stirred reactlon mixture thus obtained in the same temperature range, a solution of 22.00 g (102 m mol) of 4-chlorophenylsulfonyl ~ethylisocyanide in 220 ml of methylene chloride ~as added dropuise over 40 min. The reaction mixture was then stirred for 2 hours at the same temperature to comple~e the reaction.
Thereafter, post-treatments were conducted by similar methods as described in Example 19. 19.85 g Or 3-(2-chlorophenyl)-~ cyanopyrrole was obtained. Yield 98.0S, Melting point 138-139 C.

Example 24 :

~ --COOC2H5 ~502CH2NC

C2HsOH. CH2C12 ~ ~ CN

;'~ Sodium ethylate solution was prepared from 200 ml of ethanol and ll.60 g (200 m mol) Or metallic sodium. While being cooled at a temperature from -3 C to -2 C/ 20.10 g (100 m mol) Or alpha-cyano-cinnamic acid ethyl ester were added into the solution under stirring. To the stirred reaction mixture thus obtained in the same temperature range, a solution of 22.20 g (103 m mol) of 4-chlorophenylsulfonyl methylisocyanide in 210 ml of methylene chloride was added dropwise over 40 min. The reaction mixture was then stirred for 3 hours at the same temperature to complete the reaction.
Thereafter, post-treatments were conducted by similar methods as described in Example 19. 16.00 g Or 3-phenyl-4-cyanopyrrole ~as obtained.
Yield 95.1%, Melting point 129-130 C.

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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

l. A process for the production of a compound having the formula:

which comprises the reaction of a compound having the formula:

with a compound having the formula wherein X is the same or different substituent(s) selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylamino, C1-6 alkoxy, nitro, cyano and methylenedioxy;
COOR1 is a carboxylic acid or ester group;
R2 is C3-10 cyclic hydrocarbon group which may be substituted by substituent(s) not adversely affecting said reaction;
n is 0, 1 or 2.