CA1270851A - Trisubstituted benzoic acid intermediates - Google Patents

Abstract

TRISUBSTITUTED BENZOIC ACID INTERMEDIATES
Abstract of the Disclosure Novel trisubstituted benzoyl cyamides which are useful in the preparation of certain herbicidal 2-(2,3,4-trisubstituted benzoyl)-1,3-cyclohexanediones. The benzoyl cyamides of this invention have the following structural formula wherein R6 is chlorine, C1-C4 alkoxy or C1-C4 alkylthio:
n is the integer 0 or 2; and R7 is C1-C4 alkyl.

Description

0~

~R-7755/7756/7757/7758/7761 TRIs~ssTITuTED sENzoIc ACID rNTE~DlATEs sack~roun~ of the Invention certain 2-(2-subst~tut~d benz~yl)-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 str~ctural formula R1 R Cl R6 \~--~5 ( ) nR7 wherein R, R1, R2, R3, R4 and R5 are hydrogen or Cl-C4 alkyl; R6 is chlor-ine, C1-C4 alkoxy or Cl-C4 alkylthio; and R7 is C1-C4 alkyl; and n is the 1~ integer 0 or 2.

These herbicides can be prepared by reacting a dione of the structural fonmula R2 ~0 R ~ O

wherein R, R1, R2, R3, R4 and R5 are as defined with a mole of trisubsti-tuted '~enz~yl cyanides of the structural formula Cl R6 l ~3S(o)nR7 wherein R5 and R7 are as defined abcve.

'1~7~h~51 A slight mole excess of zinc chloride (ZnC12) is used in a suitable solvent such as methylene chloride along with the two reactants.
slight mole excess of triethylamine is slowly added to the reacticn mix-ure with cooling. me resulting mixture is stirred at roo~ temperaturefor several hours and the reaction product is worked ~p by conventional techniques.

me trisubstituted benzoyl cyanides can be prepared from their corresponding tri-substituted benzoyl chlorides which are preparable from their corresponding tri-substituted benzoic acids, according to processes described in detail hereinafter.

Description of the Invention ~ Thi~s invention relates to novel trisubstituted benzoyl cyanides which are useful in the preparation of certain herbicidal 2-(2,3,4-trisubstituted benzoyl)-l,3-cyclohexanediones, described heretofor. The intermediate benzoyl cyamides of this invention have the following formula:
Cl R6 NC-C ~ (o)nR7 wherein R6 is chlorine, Cl-C4 alkoxy or C1-C4 alkylthio; n is the integer, O or 2; and R7 is C1-C4 alkyl.
The invention also relates to novel trisubstituted benzoic acid intermediates having the fol'owing structural formula:
Il IR6 HO-C- ~ S(o)nR7 wherein R6 is chlorine, C1-C4 alh~xy or Cl-C4 alkylthio, n is the integer O or 2; and R7 is C1-C4 alkyl, preferably Cl-C3 Alkyl.

~70 2a Preferably R6 is chlorine, methoxy or ethoxy or pro~oxy; n is 2;
and R7 is methyl or ethyl~

Ihe novel inter~T ediate~ having the structural f:~mula O ~

wherein R7 is as defined are also compounds of this invention.

.~, The intermediate compounds of the present invention can be pre-pared by the general method shown in Figure 1 of the drawir~ with R, R',R" and R' ' ' being c1-c~ alkyl groups.

Referring to Figure 1 an~ particularly to Reaction Steps (A) through (I)~ consider the following: Generally in reaction step (A) mole amounts of 1-mercapto-~,3dichlorobenzene and an alkylating agent ~RX) such as C1-C4 alkyl halide, e.g.,= ethyl chloride are reacted along with a slight mole excess of an acid acceptor such as potassium carbonate. The tw~ reactants and the potassium carbonate are ccnb m ed in a sultable sol-vent such as acetonitrile. The reaction mixture is heated to akout 80Cfor 1-3 hours. The reaction product is recovered by conventional techni-ques~

For reaction (B) ~ the 1-(C1-C4-al~yIthio~-2r3_dichlorobenzene (1 mole) and acetyl chlcride ~2 moles) are reacted along with 2 moles of aluminum chloride or zinC chloride added slowly in a suitable solvent such as ethylene chloride or methylene chloride at a temperature of about 0 to 5C for 1-2 hours. After the reaction mixture is allowed to wann to roam temperature, it is added to a mixture of ice and 2 normal hydrochloric acid. ~queous and solvent la~ers fonm and are separated. me desired 4-(C1-C4-alkylthio)-2,~-di~hloroacetophenone is re~overed from the solvent by conventional techniques.

The novel intermediate ccmpounds, 4-~C1-C4-alkylthio)-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 tB) with at least a mole amount of icdine in pyridine followed by hydrolysis with sodium hydroxide in a manner as described by L.C. King, J. hmer. Chen. Soc., 66, 894 (1944~. The desired intermedi-.
ate compounds are recovered by conventional techniques~

In the alternative, another ncvel intenmediate compound 4-(Cl-C4_ alkylsulfonyl)-2,3-dichlorobenzoic acid can be prepared in reaction step (D) by oxidizing a mole amount of 4-(Cl-C4-alkylthio)-2,3-dichloroaceto-phenone prepared in reaction step (B) with at least 5 moles of an oxidiz-ing agent such as scdium hypochlorite in a suitable solvent such as 3L~ 7 ~ iL

dioxane by heating a solution of the reactants to 80C. After an exo-thermic reaction, the mixture is ccoled and acidified with hydrochloric acid. The desired intermediate ~hich is a precipitate is reccvered by filtration.

S In reaction step ( E ) 4-(c1-c4-alkylsul~onyl)-2~3-dichlorobenzoic acid prepared in reaction step (D) is dissolved in a 20% aqueous solution of sodiun hydroxide and heated at reflux for 5-10 hours. The resulting mixture is cooled an~ acidified ~ith an acid such as concentrated hy~ro-chloric acid. Ihe crude acid is recovered by extracting it with ethyl acetate, follGwed by drying over magneisum sul ate and remcving the ethyl acetate under vacu~n. The desired novel intermediate product, 4-(C1-C4-alkylsulfonyl)-2-chloro-3-hydroxybenzoic acid, is obtained by recrystalli-zation ~ram 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 a~ent (R'X) (2 moles) such as Cl-C4 alkyl iodide, e.g., ethyl iodide, are reacted along with a slight mole excess of an acid acceptor such as potassium carbonate. The t~ reactants a~d the acid acceptor are c~nbined in a suitable solvent SUCh as dimethylfonmamide ar.d heated at 50-100C for 7 24 hours. After cooling, the reaCtion miXture iS partitioned between ethyl acetate and 5% potassium carbonate. The ethyl ester Of 4-(C1-C4-alkylsulfonyl)-3-(C1-C4-alkoxy)-2-chlorobenzoic acid is reccNered frcm the ethyl acetate layer by conventional techniques. Basic hydrolysis of the ester ylelds the desired intermediate acid.

In reaction step (G), mole anounts of 3-~C1-C4-alkoxy)-4-(C1-C4-al~ylsulfonyl)-2-chlorobenzoic acid prepared in reaction (F) and di-Cl-C2-alkyl sulfate (R'')2SOg along with 3 moles of potassium carbonate are stirred at roam t~perature for 0.5-1.5 hours in a suitable solvent such as dimethylformamide to forn 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 chloride and water. The methylene chloride is 7t)~3r~3L

concentrated ln 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 hydrochloric acid and extracted with methylene chloride. Two layers form and are separated. The methylene chloride layer 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-Ca-alkylthio)-2-chlorobenzoic acid and novel intermediate

3,4-bis(-C1-C4-alkylthio)-2-chlorobenzoic acid. The tw~ benzoic acids are esterified to the methyl ester with methanol and sulfuric acid in an ethylene dichloride solvent by the procedure recited in Clinton and Laskowski, J. kmer. Chem. Soc., 70, 3135 (1948). The esters are then separated by standard chromatographic 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 moles of potassium carbonate are stirred at room 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 rocm temper-ature, whereby the 4-(C1-c4-alkylsulfonyl) group of the ester is replaced with a C1-C4-alkylmercaptan group. m e reaction mixture is partitioned between methylene chloride and water. m e methylene chloride is concen-trated m vacuo to yield the crude es~er of the desired benzoic acid.
After basic hydrolysis of the ester, the desired 3-(c1-c4-alkylthio)-4 (C1-C4-alkylthioj-2-chlorobenzoic acid is obtained.

1~7 ~ 9L

The following series of examples teach the synthesis of repre-sentative com~ounds of this invention. The structures of all ccmpounds o the examples and tables were verified by nuclear ma~netic resonance (nmr), infrared spectroscopy (ir) and mass spectroscopy (ms).

,EXP~LE 1 2,3-Dichloro-4-ethylthio-acetophenone Cl Cl C 2H5S- ~H3 To a solution of the 2-ethylthio-2,3-dichlorobenzene (0.5 moles) and 78.5 grams (g) (1.0 mole) acetyl chloride ln 500 milliliters (ml) of methylene chloride at 5C was added aluminum chloride (133.5 g, 1.0 mole) portionwise, over a period of 1.0 hour. m e reaction was allowed to warm to roam temperature, and then it was slowly poured into a mixture of ice and 2N hydrochloric acid. The layers were separated and the methylene chloride layer was washed with 5% NaOH and water. After drying over mag-nesium sulfate, the methylene chloride was removed in vacuo to afford the acetophenone (114 g, 90%) as a tan solid with m.p. 53-55C.

A~ditional compounds were prepared by the sane procedure as described in Example 1 and are listed in Tahle 1.

4-Alkylthio-2,3-dichloroacetophenones Cl Cl R'S- ~ - ~/

R' Physical Constant (m.p C) -CH2CH2C~3 glass 1~ 7(3 8~il ~X~PLE 2 2!3-Dichloro-4-ethylthiobenzoic A~id Cl Cl C2H5S~--C02H

The 4-ethylthio-2,3-dichloroacetophenone prepared in Example 1 was oxidized to the corresponding acid employing iodine-pyridine and sodi~m hydroxide in a manner as described by L.C. King, J. Amer. Che~.
Soc., 66, 894 (1944). m.p. 204-206C.

5Additional comFounds were prepared by the same procedure as descri~ed in Example 2 and are listed in Table 2.

TA~3LE 2 4-Alkylthio-2,3-dichlorobenzoic Acids Cl Cl R7S~--C02H

R_ Physical Constant (m.~. C) EX~MPLE 3 4-Ethvlsulfonvl-2,3-dichlorobenzoic Acid Cl Cl C2H5so2~ C02H

A viqourously stirred mixture of the 4-ethylthio-2,3-dichloro-acetophenone prepared in Example 1 (0.25 mole), dioxane (200 ml), and 5%
scdium hypochlorite (1860 ml, 1.25 mole) was slowly heated to 80C, where-upon an exothenmic reaction ccmmenced. After the exotherm (80-100C) had subsided the reaction mixture was cooled and acidified with concentrated 1~7U~

hydrochloric acid. Filtration of the resulting precipitate then afforded the desir~d acid. m.p. 170 - 1 72C.

Pdditional ccmpounds were pre2ared by the same procedure as aescribed in xa~ple 3 ar.a are listed in Table 3.

TABL~ 3 4-Alkyl sul fonyl-2, 3-dichlorobenz~ ic Ac ids Cl Cl R7So2~--C02H

R7 Physical Constant (m.p. C~

~X~.~PLE 4 2-Chloro-4-ethylsulfonyl-3-hydroxybenzoic Acid H0 Cl C2H5So2-~3~Co2H

A solution of the 4-ethylsulfonyl-2,3-dichlorobena~ic acid pre-pared in Example 3 (0.35 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. m e ethyl acetate extracts were combined, dried cver 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. 188-192C.

Additional compounds were prepared by the sane procedure as described in Example 4 and are listed in Table 4.

1 ~ 7 0 ~3~J~

4-Alkylsulfonyl-2-chloro-3-hydroxybenzoic Acid HO fl R7S02 h~3{ o2H
\
R7 Physical Constant (m.~. C) -CH3 187-lB9 Ea~MPLE 5 3-Ethoxy-4-ethylsulfonyl-2-chloro~enzoic Acid C2H50 Cl ,L~
C2H5S02-~\,--C02H

A mixture of the 2-chloro-4-ethylsulfonyl-3-hydroxybenzoic acid prepared in E~ample 4 (0.075 mole), ethyl iodide (0.5 mole), and potassiun carbonate (0.1 mole) in dimethylformamide (150 ml) was heated at 90C for 7 hours. After cooling, the reaction mixture w~5 partitioned between

5 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 ~y stirring the ester (0.075 mole) with a base such as scdiun hydro~ide (0.1 mole) in ethanol 10 (100 ml) at room temperature for 16 hours. The reaction mixture was acid-ified with aN HCl, and then partitioned between methylene chioride and water. m e methylene chloride layer was dried over magnesi~n sulfate and concentrated in vacuo to afford the acid as an oil.

Additional compounds were prepared by the same Frocedure as described in EXample 5 and are listed in Table S.

1~ ,'U~;3:~, TABr.r~. 5 4-Plkylsulfonyl-3-alkoxy-2-chlorobenzoic Acid.
~6 C1 R7So2~3~Co2H

R7 R6 ysical Constant (m~p. C) -CH2C~3 -OCH3 127-l~O
-CH2C~3 -OCH2CH2CH3 128-132 -CH2CH2CH3 ~ocH2cH3 73--78 -CH2CH3 -oCH2CH2CH2cH3 oil -CH2CH3 -OCH2-CH-CH3 oil -CH2CH3 -OCH-CH3 oil EX~MPLE 6 3-Alkoxy-4-alkylthio-2-chlorobenzoic Acid 2H5 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 roam temperature for 1 hour to give the ethyl ester. m en etnylmercaptan (0.2 mole) was added and the reaction mixture was stirred for 4 days at room temperature to replace the 4-ethylsl1lfonyl group with a 4-ethylthio group. Ihe reaction mixture was partitioned between methylene chloride and water, and the methylene chlor-ide layer concentrated in vacuo to afford the crude product ester.
Hydrolysis of the ester to the acid was accomplished by stirring the ester h5~

(0.1 mole) with a base such as sodium hydroxide (0.1 mole) in ethanol (lO0 ml) at room temperature for 16 hours. m e reaction mixture was acidified with 2N hydrochloric acid, and then partitioned bet~een methylene chloride and water. The methylene chloride layer was dried over magnesium sulfate ; and concentrated in vacuo to afford the acid. m.p. 116-120~C.

Example 7 4-Ethylsulfonyl-3-ethylthio-2-chlorobenzoic acid and 3,4-Bis-ethylthio-2=chlorobenzoic acid C2Hsf ll C2Hsf Cl C2H5S2 ~ --C02H and C2HsS ~ ~ --C02H
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 hours. After cooling, the reaction mixture was acidified with concentrated hydrochloric acid and extracted with methylene chloride. The layers were separated, and the methylene chloride layer was dried cver magnesium sulfate. Evapr oration of the methylene chloride in 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. ~mer. Chem. Soc., 70, 3135 (1948). The esters ~ere then separated via stand æd chromatographic 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.

1~7(~

4-~lky1sulfonyl-3-alkylthio-2-chlorobenzoic Acid R6 Cl R7So2~C02H

R7 R6Physical Constant (m.p. C) CH3 -SCH2CH3 l 10-1 l 2 CH2CH3 -SCH3 oil CH2CH2C~3 -SCH2CH3 oil 3~4-Bis-alkylthio-2-chlorobenzoic ACid R6 Cl R75~i--CO ~H

R7 R6 Physical ~onstant (m p. C) -CH2CH2CH~ -SCH2CH2CH3 s~nisolid The intermediate ~enzoic acids of this invention can easily be converted to their resFective acid chlorides and then to their acid cyanides by the following two reactions. Firstr a ~ole of oxalyl chloride in a suitable solvent such as methylene chloride at a te~perature of 20 to : 5 40C for 1 to 4 hours is heated with a mole of the intermediate acid according to the following reaction scheme:
R6 Cl R6 Cl R7 (O ) nS~C-OH + /C---C ~ R7 ( ) nS~-Cl + HCl + C2 + C0 wherein n, R6 and R7 are as defined.
.
The corresponding benzoic acid cyanide can be easily be prepared - from the benzoic acid chloride by reaction with cuFous 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 + CuCl The abcve-described acid chlorides can be reacted with a 1,3-cyclohexanedione to prepare the above-described herbicidal 2,3,4-trisub, stituted benzoyl-1,3-cyclohexane diones according to the following twc-step reaction:
R1 R Cl R6 1 ) ~ + Cl ~S (O ) nR7 ~"
/ ~ (C2H5)3N

R3 R2 Rl R Cl R6 R4 ~ ~ O 1¦
- R5 C~ ~ -O--C-~ ~ S(O)nR7 Generally, in step (1) mole amo~nts 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 added to the reaction mixture with cooling. The mixture is stirred at r~cm temperature for several hours.

m e reaction product is w~rk2d up by conventional techniques.

R3 R2 R1 R Cl R6 R4 \~ ~ O l I
5/ ~ 'I ~ (c2Hs)3N
R1 R Cl R6 ~5 ( ) nR7 * = acetonecyanohy~rin or ~N

~7 ~

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., potassi~m cyanide or acetonecyanohydrin). The mixture is stirred in a reaction pot for abou~ one hour at room temperature and the desired product is reccvered by conventional techniques.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Compounds having the structural formula wherein R6 is chlorine, C1-C4 alkoxy or C1-C4 alkylthio; n is the integer 0 or 2; and R7 is C1-C4 alkyl.