Note: Descriptions are shown in the official language in which they were submitted.
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
R4 RS
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
R1 R
R2\~;o
R3 ~ O
R4 R5
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
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.
TABLE 1
4-Alkylthio-2,3-dichloroacetophenones
Cl Cl
O
R'S- ~ ~
c~3
-CH3 65-72
-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.
TABLE 2
__
4~Alkylthio-2,3~dichlorobenzoic Acids
Cl Cl
,~
R7S~=~Co2H
R7 Physical Constant (m.p. C)
_ .
-CH3 201-205 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.
TABLE 3
4-Alkylsulfonyl-Z,3-dichlorobenzoic Acids
Cl Cl
R7so2~ o2H
R7 Physical Constant (m.p. C)
__
-CH3 18g-193
-CH2CH2CH3 202-204
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
HO C1
R7So2~ C02H
R7 Physical Constant (m~E~_ C)
-CH3 187-189
-CH2CH2CH3 181-185
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~
TABLF 5
4-Alkylsulfonyl-3-alkoxy~2-chlorobenz~ic Acid.
~6 Cl
R7So2~--C02H
R7 ~6
-CH3 -OCH3 126-129
-CH3 -OCH2C~3 126-131
-CH3 -ocH2cH2c~3 118-123
-CH2CH3 -OC~13 127-130
-CH2CH3 -OC~2CH2CH3 128-132
-CH2CH2CH3 -OCH3 142-145
-CH2CH2CH3 -OCH2CH3 73-78
-CH2~H3 -ocH2cH2cH2cH3 oil
-CH2CH3 -OCH2-CH-CH3 oil
CH3
-CH2CH3 -OCH-CH3 oil
CH3
: 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
11
(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.
12
TABLE 6
4-Alkylsulfonyl-3-alkylthio-2-chlorobenzoic Acid
R6 fl
R7So2~--C02H
R7 R6 Physical Cbnstant (m.p. C~
_, ,
CH3 -SCH2CH3 110-112
CH2CH3 -SCH3 oil
CH2CH2C~3 SCH2CH3 oil
TABLE 7
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~
13
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
R4 R5
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
R4 R5
* = acetonecyanohydrin or N~
14
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.
