CA1270261A - Trisubstituted benzoic acid intermediates - Google Patents
Trisubstituted benzoic acid intermediatesInfo
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Abstract
TRISUBSTITUTED BENZOIC ACID INTERMEDIATES
Abstract of the Disclosure Novel trisubstituted benzoic acid chloride intermediates are useful in the preparation of certain herbicidal 2-(2,3,4-trisubstituted benzoyl) -1, 3-cyclohexanediones. The benzoic acid chloride intermediates of this invention have the following formula
Abstract of the Disclosure Novel trisubstituted benzoic acid chloride intermediates are useful in the preparation of certain herbicidal 2-(2,3,4-trisubstituted benzoyl) -1, 3-cyclohexanediones. The benzoic acid chloride intermediates of this invention have the following formula
Description
702~
P2-7755/7756/7757/77~/77~1 TRISUBSTITUT~D BEN~OIC ACID INTE~DIATES
Certain 2-(2-subst-tut~d benæoyl)-1,3-cycl~ohexanedione herbi-cides are described in European Patent Applications 0,135,191 and 0,137,963, published March 27, 1985 and April 24, 1985, respectively.
The herbicidal compounds can have the following structural formula R1 R Cl R6 \y~. --~S ( ) nR7 R3 ~ O
wherein R, R1, R2, R3, R4 and R5 are hydrogen or C1-C4 alkyl; R6 is chlor-ine, Cl-C4 alkoxy or C1-C4 alkylthio and R7 is Cl-C4 alkyl; and n is the integer 0 or 2.
m ese herbicides can be prepared by reacting a dione of the structural formula R2\~;o R3 ~ O
wherein R, R1, R2, R3, R4 and R5 are as defined with a mole of trisubs~i-tuted benzoyl cyanides of the structural formula Cl R6 NC-C - ~ S(O)nR7 wherein R6 and R7 are as defined above.
~Z7~2~L
A slight mole excess of zinc chloride (ZnC12) s used in a suitable solvent such as methylene chloride along with the tw~ reactants.
A slight mole excess of triethylamine is slowly added to the reacticn mix-ture with cooling. The resulting mixture is stirred at room temperature for several hours and the reaction product is worXed up by conventional techniques.
m e trisubstituted benzoyl cyanides can be prepared from their corresponding tri-substituted benaoyl chlorides which are pre~Qrable from their correspondin~ tri-substituted benzoic acids, according to processes described in detail hereinafter.
This invention relates to novel tris~bstituted benzoic acid intenmediates which are useful in the preparation of certain herbicidal
P2-7755/7756/7757/77~/77~1 TRISUBSTITUT~D BEN~OIC ACID INTE~DIATES
Certain 2-(2-subst-tut~d benæoyl)-1,3-cycl~ohexanedione herbi-cides are described in European Patent Applications 0,135,191 and 0,137,963, published March 27, 1985 and April 24, 1985, respectively.
The herbicidal compounds can have the following structural formula R1 R Cl R6 \y~. --~S ( ) nR7 R3 ~ O
wherein R, R1, R2, R3, R4 and R5 are hydrogen or C1-C4 alkyl; R6 is chlor-ine, Cl-C4 alkoxy or C1-C4 alkylthio and R7 is Cl-C4 alkyl; and n is the integer 0 or 2.
m ese herbicides can be prepared by reacting a dione of the structural formula R2\~;o R3 ~ O
wherein R, R1, R2, R3, R4 and R5 are as defined with a mole of trisubs~i-tuted benzoyl cyanides of the structural formula Cl R6 NC-C - ~ S(O)nR7 wherein R6 and R7 are as defined above.
~Z7~2~L
A slight mole excess of zinc chloride (ZnC12) s used in a suitable solvent such as methylene chloride along with the tw~ reactants.
A slight mole excess of triethylamine is slowly added to the reacticn mix-ture with cooling. The resulting mixture is stirred at room temperature for several hours and the reaction product is worXed up by conventional techniques.
m e trisubstituted benzoyl cyanides can be prepared from their corresponding tri-substituted benaoyl chlorides which are pre~Qrable from their correspondin~ tri-substituted benzoic acids, according to processes described in detail hereinafter.
This invention relates to novel tris~bstituted benzoic acid intenmediates which are useful in the preparation of certain herbicidal
2-(2,3,4-trisubstituted benzoyl)-1,3-cyclohexanediones, described hereto-forO The inteLmediate benzoic acids of this invention have the following structural formula Cl R6 HO-C ~ S(O)nR7 wherein R6 is chlorine, C1-C4 alkoxy or C1-C~ alkylthio, n is the integer O or 2; and R7 is C1-C4 alkyl, preferably C1-C3 alkyl.
Preferably R6 is chlorine, methoxy or ethoxy or propoxy; n is 2;
and R7 is methyl or ethyl.
The novel intenmediateshaving the structural formula Cl OH
HO-C - ~ S(o)~R7 wherein R7 is as defined are also compounds of this invention.
The novel intermediates having the structural formula .~
-- ~.2702~
2a . . __ :1 . Cl R6 Cl~ ()nR7 .
wherein R6 i~ Cl-C4 alkoxy or Cl-C4 alkylthio; n i5 the :; lnteger O or 2; ~d R7 i~ Cl-C~ alkyl are also compounds of this invention.
~ ~71)~6~
The intermediate camFounds of the present invention can be pre-pared by the general method shown in Figure 1 of the drawin3 ~ith R, R', R" and R " ' being C1-C~ alkyl groups.
Referring to Figure 1 and particularly to Reaction Steps (A) through (I), consider the following: Generally in reaction step (A) mole amounts of 1-mercapto-2,3dichlorobenzene and an alkylating agent (RX) such as C~-C4 alkyl halide, e.g.,= ethyl chloride are reacted along ~Jith a slight mole excess of an acid acceptor such as potassium carbonate. The two reactants and the potassium carbonate are cambined in a suitable sol-vent such as acetonitrile. The reaction mixture is heated to about 80Cfor 1-3 hours. The reaction product is recovered by conventional techni-ques.
For reaction (B), the 1-(C1-C4 alkylthio)-2,3-dichlorobenzene (1 mole) and acetyl chloride (2 moles) are reacted along with 2 moles of aluminum chloride or zinc chloride added slcwly in a suitable solvent such as ethylene chloride or methylene chloride at a temperature of about 0 to 5~C for 1-2 hours. After the reaction mixture is allowed to wanm to room temperature, it is added to a mixture of ice and 2 normal hydrcchloric acid. A4ueous and solvent layers fo~m and are separated. m e desired 4-(Cl-C4-alkylthio)-2,3-dichloroacetophenone is recovered from the solvent by conventional techniques.
The novel intermediate ccmpounds, 4-(C1-C4-alXylthio)-2,3-di-chlorobenzoic acid, can be prepared in reaction step (C) by oxidizing a mole amount of the 4-(C1-C4-alkylthio)-2,3-dichloroacetophenone prepared in reaction step (B) with at least a mole cmount of icdine in pyridine followed by hydrolysis with sodium h~droxide in a manner as described by L.C. King, J. hmer. Chem. Soc., 66, 894 (1944). The desired intermedi-__ ate campounds are recovered by conventional techniques.
In the alternative, another novel intermediate ccmpound 4-(C1-C4_ 30- alkylsulfonyl)-2,3-dichlorobenzoic acid can ke prepared in reaction step (D) by oxidizing a mole amount of 4-(C1-C4-alkylthio)-2,3-dichloroaceto-phenone prepared in reaction step (B) with at least 5 moles of an oxidiz-ing agent such as sodium hypochlorite in a suitable solvent such as ~` ~270;~6~L
dioxane by heating a solution of the reactants to 80C. After an exo-thermic reaction, the mixture is cooled and acidified with hyd-c~chloric acid. The desired intermediate which is a precipitate is recavered by filtration.
In reaction step (E) 4-(C1-C4-alkylsulfonyl)-2,3-dichlorobenzoic acid prepared in reaction step (D) is dissolv0d in a 20% aqueous solution of sodium hydroxide and heated at reflux for 5-10 hours. The resulting mixture is cooled a~d acidified with an acid such as concentrated h~dro-chloric acid. The crude acid is recovered by extracting it with ethyl acetate, followed by arying over magneisum sul~ate and removing the ethyl acetate under vacuum. The desired novel intermediate prcduct, 4-(C1-C4-alkylsulfonyl)-2-chloro-3-hydroxybenzoic acid, is obtained by recrystalli-zation ~rcm ethyl acetate.
In reaction step (F), 1 mole of 4-(C1-C4-alkylsulfonyl)-2-chloro-3-hydroxybenzoic acid prepared in reaction step (E) and an alkyla-ting agent (R'X) (2 moles) such as C1-C4 alkyl iodide, e.g., ethyl iodide, are reacted along with a slight mole excess of an acid acceptor such as potassiurn carbonate. m e two reactants and the acid acceptor are ccmbined in a suitable solvent such as dimethylformamide and heated at 50-100C for 7-24 hours. After cooling, the reaction mixture is partitioned bet~een ethyl acetate and 5% potassium carbonate. ~he ethyl ester of 4-(C1-C4-alkylsulfonyl)-3-(C1-C4-alkoxy)-2-chlorobenzoic acid is recovered fram the ethyl acetate layer by conventional techniques. Basic hydrolysis of the ester yields the desired intermediate acid.
In reaction step (G), mole amounts of 3-(C1-C4-alkoxy)-4-(C1-C4-alkylsulfonyl)-2-chlorobenzoic acid prepared in reaction (F) and di-C1-C2-alkyl sulfate (R " )2S04 along with 3 moles of potassium carbon~te are stirred at room temperature for 0.5-1.5 hours in a suitable solvent such as dimethylformamide to form the alkyl ester of the starting trisub-stituted benzoic acid. Next, 2 moles of C1-C4 alkylmercaptan (R " 'SH) is added to the reaction mixture and stirred for several days at room temper-ature, whereby the 4-(C1-C4-alkylsulfonyl) group of the ester is replaced with a C1-C4-alkylmercaptan group. The reaction mixture is partitioned between methylene c~loride and water. The methylene chloride is - gl2q~261 concentrated _ vacuo to yield the crude ester of the desired benzoic acid.
After basic hydrolysis of the ester, the desired 3-(c1-c4-alko~y)-4-(c1 C4-alkylthio)-2-chlorobenzoic acid is obtained.
In reaction step (H) a mole amount of 4-(C1-C4-alkylsulfonyl)-2,3-dichlorobenzoic acid (obtained in reaction step (D)), 5 moles of sodium hydroxide and 4 moles of C1-C4 alkyl mercaptan (R'SH) in water are heated at reflux for 24 hours. After cooling, the reaction mixture is acidified with concentrated nydrochloric acid and extracted ~ith methylene chloride. I~ layers form and are separated. The metnylene chloride la~er is dried over magnesium sulfate. The methylene chloride is stripped under vacuum to give a mixture of novel intermediate 4-(C1-C4-alk~lsul-fonyl)-3-(C1-C4-al~ylthio)-2-chlorobenzoic acid and novel intermediate
Preferably R6 is chlorine, methoxy or ethoxy or propoxy; n is 2;
and R7 is methyl or ethyl.
The novel intenmediateshaving the structural formula Cl OH
HO-C - ~ S(o)~R7 wherein R7 is as defined are also compounds of this invention.
The novel intermediates having the structural formula .~
-- ~.2702~
2a . . __ :1 . Cl R6 Cl~ ()nR7 .
wherein R6 i~ Cl-C4 alkoxy or Cl-C4 alkylthio; n i5 the :; lnteger O or 2; ~d R7 i~ Cl-C~ alkyl are also compounds of this invention.
~ ~71)~6~
The intermediate camFounds of the present invention can be pre-pared by the general method shown in Figure 1 of the drawin3 ~ith R, R', R" and R " ' being C1-C~ alkyl groups.
Referring to Figure 1 and particularly to Reaction Steps (A) through (I), consider the following: Generally in reaction step (A) mole amounts of 1-mercapto-2,3dichlorobenzene and an alkylating agent (RX) such as C~-C4 alkyl halide, e.g.,= ethyl chloride are reacted along ~Jith a slight mole excess of an acid acceptor such as potassium carbonate. The two reactants and the potassium carbonate are cambined in a suitable sol-vent such as acetonitrile. The reaction mixture is heated to about 80Cfor 1-3 hours. The reaction product is recovered by conventional techni-ques.
For reaction (B), the 1-(C1-C4 alkylthio)-2,3-dichlorobenzene (1 mole) and acetyl chloride (2 moles) are reacted along with 2 moles of aluminum chloride or zinc chloride added slcwly in a suitable solvent such as ethylene chloride or methylene chloride at a temperature of about 0 to 5~C for 1-2 hours. After the reaction mixture is allowed to wanm to room temperature, it is added to a mixture of ice and 2 normal hydrcchloric acid. A4ueous and solvent layers fo~m and are separated. m e desired 4-(Cl-C4-alkylthio)-2,3-dichloroacetophenone is recovered from the solvent by conventional techniques.
The novel intermediate ccmpounds, 4-(C1-C4-alXylthio)-2,3-di-chlorobenzoic acid, can be prepared in reaction step (C) by oxidizing a mole amount of the 4-(C1-C4-alkylthio)-2,3-dichloroacetophenone prepared in reaction step (B) with at least a mole cmount of icdine in pyridine followed by hydrolysis with sodium h~droxide in a manner as described by L.C. King, J. hmer. Chem. Soc., 66, 894 (1944). The desired intermedi-__ ate campounds are recovered by conventional techniques.
In the alternative, another novel intermediate ccmpound 4-(C1-C4_ 30- alkylsulfonyl)-2,3-dichlorobenzoic acid can ke prepared in reaction step (D) by oxidizing a mole amount of 4-(C1-C4-alkylthio)-2,3-dichloroaceto-phenone prepared in reaction step (B) with at least 5 moles of an oxidiz-ing agent such as sodium hypochlorite in a suitable solvent such as ~` ~270;~6~L
dioxane by heating a solution of the reactants to 80C. After an exo-thermic reaction, the mixture is cooled and acidified with hyd-c~chloric acid. The desired intermediate which is a precipitate is recavered by filtration.
In reaction step (E) 4-(C1-C4-alkylsulfonyl)-2,3-dichlorobenzoic acid prepared in reaction step (D) is dissolv0d in a 20% aqueous solution of sodium hydroxide and heated at reflux for 5-10 hours. The resulting mixture is cooled a~d acidified with an acid such as concentrated h~dro-chloric acid. The crude acid is recovered by extracting it with ethyl acetate, followed by arying over magneisum sul~ate and removing the ethyl acetate under vacuum. The desired novel intermediate prcduct, 4-(C1-C4-alkylsulfonyl)-2-chloro-3-hydroxybenzoic acid, is obtained by recrystalli-zation ~rcm ethyl acetate.
In reaction step (F), 1 mole of 4-(C1-C4-alkylsulfonyl)-2-chloro-3-hydroxybenzoic acid prepared in reaction step (E) and an alkyla-ting agent (R'X) (2 moles) such as C1-C4 alkyl iodide, e.g., ethyl iodide, are reacted along with a slight mole excess of an acid acceptor such as potassiurn carbonate. m e two reactants and the acid acceptor are ccmbined in a suitable solvent such as dimethylformamide and heated at 50-100C for 7-24 hours. After cooling, the reaction mixture is partitioned bet~een ethyl acetate and 5% potassium carbonate. ~he ethyl ester of 4-(C1-C4-alkylsulfonyl)-3-(C1-C4-alkoxy)-2-chlorobenzoic acid is recovered fram the ethyl acetate layer by conventional techniques. Basic hydrolysis of the ester yields the desired intermediate acid.
In reaction step (G), mole amounts of 3-(C1-C4-alkoxy)-4-(C1-C4-alkylsulfonyl)-2-chlorobenzoic acid prepared in reaction (F) and di-C1-C2-alkyl sulfate (R " )2S04 along with 3 moles of potassium carbon~te are stirred at room temperature for 0.5-1.5 hours in a suitable solvent such as dimethylformamide to form the alkyl ester of the starting trisub-stituted benzoic acid. Next, 2 moles of C1-C4 alkylmercaptan (R " 'SH) is added to the reaction mixture and stirred for several days at room temper-ature, whereby the 4-(C1-C4-alkylsulfonyl) group of the ester is replaced with a C1-C4-alkylmercaptan group. The reaction mixture is partitioned between methylene c~loride and water. The methylene chloride is - gl2q~261 concentrated _ vacuo to yield the crude ester of the desired benzoic acid.
After basic hydrolysis of the ester, the desired 3-(c1-c4-alko~y)-4-(c1 C4-alkylthio)-2-chlorobenzoic acid is obtained.
In reaction step (H) a mole amount of 4-(C1-C4-alkylsulfonyl)-2,3-dichlorobenzoic acid (obtained in reaction step (D)), 5 moles of sodium hydroxide and 4 moles of C1-C4 alkyl mercaptan (R'SH) in water are heated at reflux for 24 hours. After cooling, the reaction mixture is acidified with concentrated nydrochloric acid and extracted ~ith methylene chloride. I~ layers form and are separated. The metnylene chloride la~er is dried over magnesium sulfate. The methylene chloride is stripped under vacuum to give a mixture of novel intermediate 4-(C1-C4-alk~lsul-fonyl)-3-(C1-C4-al~ylthio)-2-chlorobenzoic acid and novel intermediate
3,4-bis(-C1-c4-alkylthio)-2-chlorobenzoic acid. m e two benzoic acids are esterified to the methyl ester with methanol a~d sulfuric acid in an ethylene dichloride solvent by the procedure recite~ in Clinton and Laskowski, J. Amer. Chem. Soc., 70, 3135 (1~48). The esters are then separated by standard chramatographic techniques. ~asic hydrolysis of the separated esters give the desired acids. The first acid, 4-(C1-C4-alkyl-sulfonyl)-3-(C1-c4-alkylthio)-2-chloro-benzoic acid, is obtained in higher amounts.
In reaction step (I), mole amounts of 3-(C1-C4-alkylthio)-4-(C1-C4-alkylsulfonyl)-2-chlorobenzoic acid prepared in reaction (H) and dialkyl sulfate (R " )2SO4 along with 3 ~oles of potassium carbonate are stirred at rocm temperature for 0.5-1.5 hours in a suitable solvent such as dimethylformamide to form the ethyl ester of the starting trisubsti-tuted benzoic acid. Next, 2 moles of C1 C4 alkylmercaptan (R " 'SH) is added to the reaction mixture and stirred for several days at room tem~er-ature, whereby the 4-(C1-C4-alkylsulfonyl) group-of the ester is replaced with a Cl-C4-alkylmercaptan group. The reaction mixture is partitioned 30 bet~een methylene chloride and water. The methylene chloride is concenr ~~
trated in vacuo to yield the cru~e ester of the desired benzoic acid.
After basic hydrolysis of the ester, the desired 3-(c1-c4-alkylthio)-4 (Cl-C4-alkylthio)-2-chlorobenzoic acid is obtained.
7021~
The followin~ series of examp]es teach the synthesis of repre-sentative compourds of this invention. me st,ructures of all comFounas sf the examples and tables were verified by nuclear ma~netic resonance (~mr) J
infrared spectroscopy (ir) and mass spectroscopy (ms).
-Cl Cl C2HsS- ~ .H3 To a solution of the 2-ethylthio-2,3-dichlorGbe~zene (0.5 moles) and 78.5 gr~ms (g) (1.0 mole) acetyl chloride in 500 millili~ers (ml) of methylene chloride at 5C was added aluminum chloride (133.5 g, 1.0 mole) portionwise~ over a period of 1.0 hour. The reaction was allowed to war~
to room temperature, and then it was slowly poured into a mixture of ice and 2N hydrochloric acid. Ihe layers were separated and the methylene chloride layer was washed with 5~ NaOH and water. After drying over mag-nesiun sulfate, the methylene chloride was remcved _ vacuo ~o afford the acetophenone (114 g, 90%) as a tan solid with m.p. 53-55C.
Additional ccmpounds were prepared by the same procedure as described in Example 1 and are listed in Tahle 1.
In reaction step (I), mole amounts of 3-(C1-C4-alkylthio)-4-(C1-C4-alkylsulfonyl)-2-chlorobenzoic acid prepared in reaction (H) and dialkyl sulfate (R " )2SO4 along with 3 ~oles of potassium carbonate are stirred at rocm temperature for 0.5-1.5 hours in a suitable solvent such as dimethylformamide to form the ethyl ester of the starting trisubsti-tuted benzoic acid. Next, 2 moles of C1 C4 alkylmercaptan (R " 'SH) is added to the reaction mixture and stirred for several days at room tem~er-ature, whereby the 4-(C1-C4-alkylsulfonyl) group-of the ester is replaced with a Cl-C4-alkylmercaptan group. The reaction mixture is partitioned 30 bet~een methylene chloride and water. The methylene chloride is concenr ~~
trated in vacuo to yield the cru~e ester of the desired benzoic acid.
After basic hydrolysis of the ester, the desired 3-(c1-c4-alkylthio)-4 (Cl-C4-alkylthio)-2-chlorobenzoic acid is obtained.
7021~
The followin~ series of examp]es teach the synthesis of repre-sentative compourds of this invention. me st,ructures of all comFounas sf the examples and tables were verified by nuclear ma~netic resonance (~mr) J
infrared spectroscopy (ir) and mass spectroscopy (ms).
-Cl Cl C2HsS- ~ .H3 To a solution of the 2-ethylthio-2,3-dichlorGbe~zene (0.5 moles) and 78.5 gr~ms (g) (1.0 mole) acetyl chloride in 500 millili~ers (ml) of methylene chloride at 5C was added aluminum chloride (133.5 g, 1.0 mole) portionwise~ over a period of 1.0 hour. The reaction was allowed to war~
to room temperature, and then it was slowly poured into a mixture of ice and 2N hydrochloric acid. Ihe layers were separated and the methylene chloride layer was washed with 5~ NaOH and water. After drying over mag-nesiun sulfate, the methylene chloride was remcved _ vacuo ~o afford the acetophenone (114 g, 90%) as a tan solid with m.p. 53-55C.
Additional ccmpounds were prepared by the same procedure as described in Example 1 and are listed in Tahle 1.
4-Alkylthio-2,3-dichloroacetophenones Cl Cl O
R'S- ~ ~
c~3 -CH2CH2CH3 glass 7~2gE~
EX~MPLE 2 2,3-Dichloro-4-ethylthiobenzoic Acid C~CI
C2H5S~\ ~ -C02H
The 4-ethylthio-2,3-dichloroacetophenone prepared in E~ample 1 was oxidized to the corresponding acid employing iodine-pyridine and sodi~m hydroxide in a manner as described by L.C. King, J. ~mer. ~ne~.
S , 66, 894 (1944). m.p. 204-206C~
S Additional ccm~ounds were prepared by the same procedure as described in Example 2 and are listed in Table 2.
__ 4~Alkylthio-2,3~dichlorobenzoic Acids Cl Cl ,~
R7S~=~Co2H
R7 Physical Constant (m.p. C) _ .
-CHzCH2CH3 188-190C
EX~MPLE 3 4-Ethvlsulfonvl-2,3-dichlorobenzoic Acid Cl Cl I I
C2H5S02~/~ C02H
A vigourously stirred mixture of the 4-ethylthio-2,3-dichloro-acetophenone prepared in Example 1 (0.25 mole)~ dioxane (200 ml), and 5%
- sodium hypochlorite (1860 ml, 1.25 mole) was slowly heated to 80C, where-upon an exothermic reaction commenced. After the exothenm (80-100C) had subsided the reaction mixture was cooled and acidified with concentrated 26~
hydrochloric acid. Filtration of the resulting precipitate then afforded the desired acid. m.p. 170-172C.
Pdditional compounds were prepa~ed by the same procedure as described in Exa~ple 3 and are listed in Table 3.
4-Alkylsulfonyl-Z,3-dichlorobenzoic Acids Cl Cl R7so2~ o2H
R7 Physical Constant (m.p. C) __ -CH3 18g-193 EXAI~PLE 4 2-Chloro-4-ethylsulfonyl-3-h~droxybenzoic Acid HO ll C2H5SC)2~ C02H
A solution of the 4-ethylsulfonyl-2,3-dichlorobenzoic acid pre-pared in Example 3 (0.3S mole) in 500 ml of 20% sodium hydroxide was heated at reflux for 7 hours. After cooling, the aqueous solution was acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate extracts were co~bined, dried over m~gnesium sulfate, and concentrated in vacuo to afford the crude acid.
Recrystallization of the crude acid from ethyl acetate afforded the desired pure acid as white crystals~ m.p. 188-192~C.
A~ditional ccmpounds were prepared by the same procedure as described in Example 4 and are listed in Table 4.
TAB~E 4 4-Alkylsulfonyl-2-chloro-3-hydroxybenzoic Acid R7So2~ C02H
R7 Physical Constant (m~E~_ C) EX~XPLE S
C2H5 Cl /~
C2H5S02-~ \~--C02H
A mixture of the 2-chloro-4-ethylsulfonyl-3-hydroxybenzoic acid prepared in Example 4 (0.075 mole), ethyl iodide (O.S mole), and potassium carbonate (0.1 mole) in dimethylformamide (150 ml) was heated at 90C for 7 hours. After cooling, the reaction mixture w~s partitioned between S ethyl acetate and 5% potassium carbonate. The ethyl acetate layer was then washed with brine, dried over magnesium sulfate, and concentrated m vacuo to afford the crude ethyl ester of the desired benzoic acid. Hydro-lysis of the ester to the acid was acccmplished by stirring the ester (0.075 mole) with a base such as scdium hydroxide (0.1 mole) in ethanol (100 ml) at room temperature for 16 hours. m e reaction mixture was acid-ified with 2N HCl, and then partitioned betw~en methylene chioride and water. m e methylene chloride layer was dried over magnesiun sulfate and concentrated _ vacuo to afford the acid as an oil.
~ Additional c~mpounds were prep2red by the same procedure as described in Example 5 and are listed in Table 5.
, 6~
4-Alkylsulfonyl-3-alkoxy~2-chlorobenz~ic Acid.
~6 Cl R7So2~--C02H
R7 ~6 -CH3 -OCH2C~3 126-131 -CH3 -ocH2cH2c~3 118-123 -CH2CH3 -OC~13 127-130 -CH2CH3 -OC~2CH2CH3 128-132 -CH2~H3 -ocH2cH2cH2cH3 oil -CH2CH3 -OCH2-CH-CH3 oil -CH2CH3 -OCH-CH3 oil : Ex~MæLE 6 3-Alkoxy-4-alkylthio-2-chlorobenzoic Acid C2HsO Cl C2H5S~--C02H
A mixture of the 3-ethoxy-4-ethylsulfonyl-2-chlorobenzoic acid (0.1 mole), potassium carbonate (0.3 mole), diethylsulfate (0.1 mole) and dimethylforamide (150 ml) was stirred at r temperature for 1 hour to give the ethyl esterO Then ethylmercaptan (0.2 mole) was added and the reaction mixture was stirred for 4 days at rocm temperature to replace the 4-ethylsulfonyl group with a 4-ethylthio group. The reaction mixture was partitioned between methylene chloride and water, and the methylene chlor-iae layer concentrated in vacuo to afford the crude prcduct ester.
Hydrolysis of the ester to the acid was acccmplished by stirring the ester (0.1 mole) with a base such as scdium hydroxide (0.1 mole) in ethar.ol (100 ml) at rocm temperature for 16 hours. m e reaction mixture was acidified with 2N hydrochloric acid, and then partitioned between methylene chloride and water. The methylene chloride layer was dried c~er magnesium sulfate and concentrated ln vacuo to afford the acid. m.p. 116-120C.
4-Ethylsulfonyl-3-ethylthio-2-chlorobenzoic acid and C2H5S ICl C2H5f Cl C2H5S02 ~ --C02H and C2HsS ~ r ~ ~CO2H
A solution of the 4-ethylsulfonyl-2,3-dichloroben~oic acid pre-pared in Example 3 (0.2 mole), ethyl mercaptan (0.8 mole), sodium hydrox-ide (1 mole) in water (300 ml~ was heated at reflux for 24 hoursO After cooling, the reaction mixture was acidified with concentrated hydrochlorlc acid and extracted with methylene chloride. The layers were separated, and the methylene chloride layer was dried over magnesium sulfate. Evap-oration of the methylene chloride ln vacuo then afforded a mixture of the ' acids which were esterified to the methyl esters with methanol and sulfur-ic acid in ethylene dichloride by the procedure of Clinton and Lawkowski, J. hmer. Chem. Soc., 70, 3135 (1948). The esters ~1ere then separated via standard chrcmatographic techniques. Basic hydrolysis of each methyl ester then afforded the 3,4-bis-ethylthio-2-chlorobenzoic acid, m.p.
73-75C and 2-chloro-4-ethylsulfonyl-3-ethylthio-benzoic acid oil~
Additional compounds were prepared by the same procedure as described in Example 7 and are listed in Tables 6 and 7.
4-Alkylsulfonyl-3-alkylthio-2-chlorobenzoic Acid R6 fl R7So2~--C02H
R7 R6 Physical Cbnstant (m.p. C~
_, , CH2CH3 -SCH3 oil CH2CH2C~3 SCH2CH3 oil 3,4-Bis-alkylthio-2-chlorobenzoic Acid R6 Cl R7S ~ :-CO2H
R7 R6 Physical Constant (m.p. C) -CH2CH2CH3-SCH2CH2CH3 semisolid The intermediate benzoic acids of this invention can easily be converted to their respective acid chlorides and then to their acid cyanides by the following two reactions. First, a mole of cxalyl chloride in a suitable solvent such as methylene chloride at a te~perature of 20 to 40C for 1 to 4 hours is heated with a mole of the intermediate acid according to the following reaction scheme:
R6 ClR6 Cl '' o O O I i O
R7(o)nS~E~ + ~C--~ ~ R7(0)nS~-Cl + HCl + CO2 + CO
wherein n, R6 an~ R7 are as defined.
The corresponding benzoic acid cyanide can be easily be preparea frcm the benzoic acid chloride by reaction with cupous cyanide at a tem-perature of 150 to 220C for 1 to 2 hours according to the following reac-tion:
7~
R6 Cl ,R6 Cl ~ ' O ' ' O
R7(o)nS ~ -Cl + CuCN ~ R7(O)nS-~ ~ -CN f CuCl The abcve-described ac'd chlorides can be reacted with a 1,3-cyclohexanedione to prepare the abave-described herbicidal 2,3,4-trisub-stituted benzoyl-1,3-cyclohexane diones according to the ollowing t~
step reaction:
R1 R Cl R6 R2 \~/ ~ o O !--Cl-C~S (O ) n~7 (C2H5)3N
R3 R2 R1 R Cl R6 R4 \ _ ~ O I I
\~-O--C-~S ( ) nR7 Generally, in step (1) mole amounts of the dione and substituted benzoyl chloride are used, along with a slight mole excess of triethyl-amine. The two reactants are ccmbined in a solvent such as methylene chloride. The triethylamine is slowly ~dded to the reaction mixture with cooling. The mixture is stirred at room temperature for several hours.
The reaction product is w~rked up by conventional techniques.
R3 R2 R1 R Cl R6 R4 \I ~ O I i ` /~ !l ~S ()n~7 ~
Rl R Cl R6 R2~ O O ,_1 3/ ~ ~ S(o)nR7 * = acetonecyanohydrin or N~
Generally, in step (2) a mole of the enol ester intermediate is reacted with 1 to 4 moles of the triethylamine, preferably 2 moles of the triethylamine and up to 0.5 mole, preferably 0.1 mole of a cyanide source ~e.g., potassium cyanide or acetonecyanohydrin). ~he mixture is stirred in a reaction pot for about one hour at room temperature and the desired product is reccvered by conventional techniques.
R'S- ~ ~
c~3 -CH2CH2CH3 glass 7~2gE~
EX~MPLE 2 2,3-Dichloro-4-ethylthiobenzoic Acid C~CI
C2H5S~\ ~ -C02H
The 4-ethylthio-2,3-dichloroacetophenone prepared in E~ample 1 was oxidized to the corresponding acid employing iodine-pyridine and sodi~m hydroxide in a manner as described by L.C. King, J. ~mer. ~ne~.
S , 66, 894 (1944). m.p. 204-206C~
S Additional ccm~ounds were prepared by the same procedure as described in Example 2 and are listed in Table 2.
__ 4~Alkylthio-2,3~dichlorobenzoic Acids Cl Cl ,~
R7S~=~Co2H
R7 Physical Constant (m.p. C) _ .
-CHzCH2CH3 188-190C
EX~MPLE 3 4-Ethvlsulfonvl-2,3-dichlorobenzoic Acid Cl Cl I I
C2H5S02~/~ C02H
A vigourously stirred mixture of the 4-ethylthio-2,3-dichloro-acetophenone prepared in Example 1 (0.25 mole)~ dioxane (200 ml), and 5%
- sodium hypochlorite (1860 ml, 1.25 mole) was slowly heated to 80C, where-upon an exothermic reaction commenced. After the exothenm (80-100C) had subsided the reaction mixture was cooled and acidified with concentrated 26~
hydrochloric acid. Filtration of the resulting precipitate then afforded the desired acid. m.p. 170-172C.
Pdditional compounds were prepa~ed by the same procedure as described in Exa~ple 3 and are listed in Table 3.
4-Alkylsulfonyl-Z,3-dichlorobenzoic Acids Cl Cl R7so2~ o2H
R7 Physical Constant (m.p. C) __ -CH3 18g-193 EXAI~PLE 4 2-Chloro-4-ethylsulfonyl-3-h~droxybenzoic Acid HO ll C2H5SC)2~ C02H
A solution of the 4-ethylsulfonyl-2,3-dichlorobenzoic acid pre-pared in Example 3 (0.3S mole) in 500 ml of 20% sodium hydroxide was heated at reflux for 7 hours. After cooling, the aqueous solution was acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate extracts were co~bined, dried over m~gnesium sulfate, and concentrated in vacuo to afford the crude acid.
Recrystallization of the crude acid from ethyl acetate afforded the desired pure acid as white crystals~ m.p. 188-192~C.
A~ditional ccmpounds were prepared by the same procedure as described in Example 4 and are listed in Table 4.
TAB~E 4 4-Alkylsulfonyl-2-chloro-3-hydroxybenzoic Acid R7So2~ C02H
R7 Physical Constant (m~E~_ C) EX~XPLE S
C2H5 Cl /~
C2H5S02-~ \~--C02H
A mixture of the 2-chloro-4-ethylsulfonyl-3-hydroxybenzoic acid prepared in Example 4 (0.075 mole), ethyl iodide (O.S mole), and potassium carbonate (0.1 mole) in dimethylformamide (150 ml) was heated at 90C for 7 hours. After cooling, the reaction mixture w~s partitioned between S ethyl acetate and 5% potassium carbonate. The ethyl acetate layer was then washed with brine, dried over magnesium sulfate, and concentrated m vacuo to afford the crude ethyl ester of the desired benzoic acid. Hydro-lysis of the ester to the acid was acccmplished by stirring the ester (0.075 mole) with a base such as scdium hydroxide (0.1 mole) in ethanol (100 ml) at room temperature for 16 hours. m e reaction mixture was acid-ified with 2N HCl, and then partitioned betw~en methylene chioride and water. m e methylene chloride layer was dried over magnesiun sulfate and concentrated _ vacuo to afford the acid as an oil.
~ Additional c~mpounds were prep2red by the same procedure as described in Example 5 and are listed in Table 5.
, 6~
4-Alkylsulfonyl-3-alkoxy~2-chlorobenz~ic Acid.
~6 Cl R7So2~--C02H
R7 ~6 -CH3 -OCH2C~3 126-131 -CH3 -ocH2cH2c~3 118-123 -CH2CH3 -OC~13 127-130 -CH2CH3 -OC~2CH2CH3 128-132 -CH2~H3 -ocH2cH2cH2cH3 oil -CH2CH3 -OCH2-CH-CH3 oil -CH2CH3 -OCH-CH3 oil : Ex~MæLE 6 3-Alkoxy-4-alkylthio-2-chlorobenzoic Acid C2HsO Cl C2H5S~--C02H
A mixture of the 3-ethoxy-4-ethylsulfonyl-2-chlorobenzoic acid (0.1 mole), potassium carbonate (0.3 mole), diethylsulfate (0.1 mole) and dimethylforamide (150 ml) was stirred at r temperature for 1 hour to give the ethyl esterO Then ethylmercaptan (0.2 mole) was added and the reaction mixture was stirred for 4 days at rocm temperature to replace the 4-ethylsulfonyl group with a 4-ethylthio group. The reaction mixture was partitioned between methylene chloride and water, and the methylene chlor-iae layer concentrated in vacuo to afford the crude prcduct ester.
Hydrolysis of the ester to the acid was acccmplished by stirring the ester (0.1 mole) with a base such as scdium hydroxide (0.1 mole) in ethar.ol (100 ml) at rocm temperature for 16 hours. m e reaction mixture was acidified with 2N hydrochloric acid, and then partitioned between methylene chloride and water. The methylene chloride layer was dried c~er magnesium sulfate and concentrated ln vacuo to afford the acid. m.p. 116-120C.
4-Ethylsulfonyl-3-ethylthio-2-chlorobenzoic acid and C2H5S ICl C2H5f Cl C2H5S02 ~ --C02H and C2HsS ~ r ~ ~CO2H
A solution of the 4-ethylsulfonyl-2,3-dichloroben~oic acid pre-pared in Example 3 (0.2 mole), ethyl mercaptan (0.8 mole), sodium hydrox-ide (1 mole) in water (300 ml~ was heated at reflux for 24 hoursO After cooling, the reaction mixture was acidified with concentrated hydrochlorlc acid and extracted with methylene chloride. The layers were separated, and the methylene chloride layer was dried over magnesium sulfate. Evap-oration of the methylene chloride ln vacuo then afforded a mixture of the ' acids which were esterified to the methyl esters with methanol and sulfur-ic acid in ethylene dichloride by the procedure of Clinton and Lawkowski, J. hmer. Chem. Soc., 70, 3135 (1948). The esters ~1ere then separated via standard chrcmatographic techniques. Basic hydrolysis of each methyl ester then afforded the 3,4-bis-ethylthio-2-chlorobenzoic acid, m.p.
73-75C and 2-chloro-4-ethylsulfonyl-3-ethylthio-benzoic acid oil~
Additional compounds were prepared by the same procedure as described in Example 7 and are listed in Tables 6 and 7.
4-Alkylsulfonyl-3-alkylthio-2-chlorobenzoic Acid R6 fl R7So2~--C02H
R7 R6 Physical Cbnstant (m.p. C~
_, , CH2CH3 -SCH3 oil CH2CH2C~3 SCH2CH3 oil 3,4-Bis-alkylthio-2-chlorobenzoic Acid R6 Cl R7S ~ :-CO2H
R7 R6 Physical Constant (m.p. C) -CH2CH2CH3-SCH2CH2CH3 semisolid The intermediate benzoic acids of this invention can easily be converted to their respective acid chlorides and then to their acid cyanides by the following two reactions. First, a mole of cxalyl chloride in a suitable solvent such as methylene chloride at a te~perature of 20 to 40C for 1 to 4 hours is heated with a mole of the intermediate acid according to the following reaction scheme:
R6 ClR6 Cl '' o O O I i O
R7(o)nS~E~ + ~C--~ ~ R7(0)nS~-Cl + HCl + CO2 + CO
wherein n, R6 an~ R7 are as defined.
The corresponding benzoic acid cyanide can be easily be preparea frcm the benzoic acid chloride by reaction with cupous cyanide at a tem-perature of 150 to 220C for 1 to 2 hours according to the following reac-tion:
7~
R6 Cl ,R6 Cl ~ ' O ' ' O
R7(o)nS ~ -Cl + CuCN ~ R7(O)nS-~ ~ -CN f CuCl The abcve-described ac'd chlorides can be reacted with a 1,3-cyclohexanedione to prepare the abave-described herbicidal 2,3,4-trisub-stituted benzoyl-1,3-cyclohexane diones according to the ollowing t~
step reaction:
R1 R Cl R6 R2 \~/ ~ o O !--Cl-C~S (O ) n~7 (C2H5)3N
R3 R2 R1 R Cl R6 R4 \ _ ~ O I I
\~-O--C-~S ( ) nR7 Generally, in step (1) mole amounts of the dione and substituted benzoyl chloride are used, along with a slight mole excess of triethyl-amine. The two reactants are ccmbined in a solvent such as methylene chloride. The triethylamine is slowly ~dded to the reaction mixture with cooling. The mixture is stirred at room temperature for several hours.
The reaction product is w~rked up by conventional techniques.
R3 R2 R1 R Cl R6 R4 \I ~ O I i ` /~ !l ~S ()n~7 ~
Rl R Cl R6 R2~ O O ,_1 3/ ~ ~ S(o)nR7 * = acetonecyanohydrin or N~
Generally, in step (2) a mole of the enol ester intermediate is reacted with 1 to 4 moles of the triethylamine, preferably 2 moles of the triethylamine and up to 0.5 mole, preferably 0.1 mole of a cyanide source ~e.g., potassium cyanide or acetonecyanohydrin). ~he mixture is stirred in a reaction pot for about one hour at room temperature and the desired product is reccvered by conventional techniques.
Claims
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Compounds having the structural formula wherein R6 is C1-C4 alkoxy or C1-C4 alkylthio; n is the integer 0 or 2; and R7 is C1-C4 alkyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000599512A CA1270261A (en) | 1985-03-07 | 1989-05-11 | Trisubstituted benzoic acid intermediates |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/709,006 US4898973A (en) | 1985-03-07 | 1985-03-07 | Trisubstituted benzoic acid intermediates |
| US709,006 | 1985-03-07 | ||
| CA000503424A CA1266485A1 (en) | 1985-03-07 | 1986-03-06 | Trisubstituted benzoic acid intermediates |
| CA000599512A CA1270261A (en) | 1985-03-07 | 1989-05-11 | Trisubstituted benzoic acid intermediates |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000503424A Division CA1266485A1 (en) | 1985-03-07 | 1986-03-06 | Trisubstituted benzoic acid intermediates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1270261A true CA1270261A (en) | 1990-06-12 |
Family
ID=25670929
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000599512A Expired - Lifetime CA1270261A (en) | 1985-03-07 | 1989-05-11 | Trisubstituted benzoic acid intermediates |
| CA000599513A Expired - Lifetime CA1270851A (en) | 1985-03-07 | 1989-05-11 | Trisubstituted benzoic acid intermediates |
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| Application Number | Title | Priority Date | Filing Date |
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| CA000599513A Expired - Lifetime CA1270851A (en) | 1985-03-07 | 1989-05-11 | Trisubstituted benzoic acid intermediates |
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|---|---|
| CA (2) | CA1270261A (en) |
-
1989
- 1989-05-11 CA CA000599512A patent/CA1270261A/en not_active Expired - Lifetime
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|---|---|
| CA1270851A (en) | 1990-06-26 |
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