WO1991013065A1 - 6-aryl-2-substituted benzoic acid herbicides - Google Patents

Abstract

Compound of formula (I) in which A is O, S, or -N-R2 in which R2 is hydrogen, alkyl, -C(O)-NH¿2? or -C(O)alkyl; B is -CH-, -CR?4¿- or -N-; R and R1 are independently alkyl, alkoxy, haloalkoxy, halogen or alkylamino; and R4 is hydrogen, alkyl, phenyl, nitro, cyano, amino, alkoxycarbonyl, or halogen; M is hydrogen, alkyl, alkenyl, alkynyl, phenylalkyl, haloalkyl, cyanoalkyl, alkylthioalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, alkoxycarbonylalkyl, carboxyalkyl, di(alkoxycarbonyl)alkyl, dialkylaminocarbonylalkyl, dialkylideneamino, alkylthioalkylideneamino, optionally alkyl substituted ammonium, optionally hydroxyalkyl substituted ammonium, the cation of an alkali or alkaline earth metal, or phenyl optionally substituted with nitro, halo, alkyl, haloalkyl or alkyloxy; and Q is (II), in which X, Y, and P are independently hydrogen, halogen, lower alkyl, lower alkoxy, lower haloalkyl, lower alkylthio, lower alkylsulfonyl, alkylsufonylamino, alkylsulfonyloxy, arylsulfonyloxy, di(aryl sulfonyl)amino, benzylamino, alkylcarbonylamino, aminocarbonylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylsulfonylamino, phenylsulfonylamino, acid salts of the noted amino compounds, lower alkenyl, lower alkynyl, lower alkenyloxy, lower alkynyloxy, cyano, nitro or amino, or X and Y taken together form a C¿1? to C3 alkylenedioxy heterocyclic ring; or an aromatic heterocycle selected from thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine.

Description

6-ARYL-2-SUBSTITUTED BENZOIC ACID HERBICIDES

This invention provides compounds of the following Formula I which are useful as herbicides:

Formula I

in which

A is O, S, or -N-R² in which R² is hydrogen, alkyl (for example, methyl or ethyl), -C(O)NH₂, or -C(O)-alkyl (for example, -C(O)-CH₃);

B is -CH-, -CR⁴- or -N-;

R and R¹ are independently alkyl (for example, methyl), alkoxy (for example, methoxy), haloalkoxy (for example, -OCHF₂ or -OCH₂CH₂Cl), or alkylamino (for example, -NHCH₃ or -N(CH₃)₂); halogen; and

R⁴ is hydrogen, alkyl, phenyl, nitro, cyano, amino, alkoxycarbonyl, or halogen;

M is hydrogen, alkyl, alkenyl, alkynyl, phenylalkyl, haloalkyl, cyanoalkyl, alkylthioalkyl, dialkylamino- alkyl, alkylsulfonylalkyl, alkoxycarbonylalkyl, carboxy- alkyl, di(alkoxycarbonyl) alkyl, dialkylaminocarbonyl- alkyl, dialkylideneamino, alkylthioalkylideneamino, optionally alkyl substituted ammonium, optionally hydroxyalkyl substituted ammonium, the cation of an alkali or alkaline earth metal, or phenyl optionally substituted with nitro, halo, alkyl, haloalkyl or alkyloxy; and

Q is Formula II

in which X, Y, and P are independently hydrogen, halogen (for example, chlorine and fluorine), lower alkyl (for example, methyl), lower alkoxy (for example, methoxy ), cyano, nitro, amino, lower haloalkyl (for example, trifluoromethyl or difluoromethyl), lower haloalkoxy (for example, trifluoromethoxy or difluoromethoxy), lower alkylthio (for example, methylthio), lower

alkylsulfonyl (for example, methylsulfonyl),

alkylsulfonylamino, alkylsulfonyloxy, arylsulfonyloxy, di(aryl sulfonyl) amino, benzylamino, alkylcarbonylamino, aminocarbonylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylsulfonylamino, phenylsulfonylamino, acid salts of the noted amino compounds, lower alkenyl (for example, vinyl or methylvinyl), lower alkynyl (for example, ethynyl or propargyl), lower alkenyloxy (for example, 2- propenyl) or lower alkynyloxy (for example,

propargyloxy), or X and Y taken together form a C₁-C₃ alkylenedioxy heterocyclic ring (for example,

benzodioxole); or

Q is a 5- or 6-membered aromatic heterocyclic ring selected from thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine;

and having the formula

in which X', Y', W, V, U, X", Y", W, V and Z are independently nitrogen, oxygen, sulfur, -CH- or -CR³ in which R³ is halogen (for example, chlorine or fluorine), lower alkyl (for example, methyl or isopropyl), lower alkoxy (for example, methoxy) or lower haloalkoxy (for example, difluoromethoxy).

In each aspect of the invention it is often prefer- able that any alkyl, alkynyl or alkenyl moiety,

including the hydrocarbon moiety of any alkoxy group, is a lower alkyl group having less than 6 carbon atoms, and preferably 1 to 3 carbon atoms.

Compounds of this invention which are shown in

Formula I may be prepared using the following compounds

in which A, B, Q, R, and R¹ are the same as indicated in Formula I, and T is an acid precursor or derivative such as formyl, cyano, methylcarbonyl, dialkoxymethyl, alkyloxycarbonyl, aryloxycarbonyl, alkyl or halogen.

The carboxy compounds of Formula I may be prepared, depending on the T substituent, by oxidation of the formyl group; hydrolysis of the cyano, aryloxycarbonyl or alkyloxycarbonyl groups; hydrolysis of the

dialkoxymethyl substituent to form the aldehyde followed by oxidation to the acid; oxidation of the

methylcarbonyl substituent using a hypohalite; or substitution of the halogen using an alkyl lithium compound followed by treatment with carbon dioxide and acid.

Compounds of Formula IV in which T is formyl, cyano, methylcarbonyl, dialkoxymethyl, alkyloxycarbonyl, aryloxycarbonyl, -C(O)OH, -C(O)OM or halogen may be prepared in the following reaction

in which G is a leaving group such as chloro or

methylsulfonyl. Any of a variety of bases may be used including the alkali or alkaline earth metal carbonates, hydrides, hydroxides, or lower dialkylamines. Specific examples include the carbonates and hydroxides of sodium, potassium, lithium and calcium; the hydrides of sodium, lithium, and potassium; and lithium, sodium, or magnesium diisopropylamide.

The compounds of Formula I having an oxygen bridge may also be prepared by reacting an optionally

substituted ortho-fluorobenzaldehyde with potassium hydroxide to form the corresponding optionally

substituted salicylaldehyde. The optional substituent is preferably in, but not limited to, the 6-position. Thus, the product of the foregoing reaction would be a 6-optionally substituted salicylaldehyde. The 6- optionally substituted salicylaldehyde is in turn reacted with an inorganic base, for example potassium carbonate or sodium hydride, and an appropriately substituted heterocycle having a leaving group, such as chloro or methylsulfonyl, at the 2-position of the heterocyclic ring (for example 4,6-dimethoxy-2- methylsulfonylpyrimidine or 2-chloro-4,6-dimethoxy-

1,3,5-triazine) to yield the corresponding benzaldehyde (for example 6-optionally substituted 2-(4,6- dimethoxypyrimidin-2-yloxy)benzaldehyde or 2-(4,6- dimethoxy-1,3,5-triazin-2-yloxy)benzaldehyde,

respectively). The benzaldehyde is then oxidized to afford the corresponding benzoic acid.

The benzoic acid compounds of Formula I having an oxygen or nitrogen bridge may be prepared by reacting a benzyl 6-substituted salicylate or anthranilate, respectively, with sodium hydride and the appropriately substituted heterocycle (for example 4,6-dimethoxy-2- methylsulfonylpyrimidine) to yield the corresponding benzoate (for example benzyl 6-substituted 2-(4,6- dimethoxypyrimidin-2-yloxy)benzoate or 2-(4,6- dimethoxypyrimidin-2-ylamino) benzoate, respectively). The benzoate is subjected to hydrogenolysis in the presence of palladium on carbon to yield the

corresponding benzoic acid (for example 6-substituted 2- (4,6-dimethoxypyrimidin-2-yloxy)benzoic acid or 2-(4,6- dimethoxypyrimidin-2-ylamino)benzoic acid,

respectively).

The benzoic acid compound of Formula I having a sulfur bridge may be prepared by reacting 6-optionally substituted anthranilic acid hydrochloride with

fluoboric acid and sodium nitrite to yield the

corresponding diazonium salt, 2-carboxy-3-optionally substituted benzenediazonium tetrafluoborate. The diazonium salt is in turn reacted with ethylxanthic acid potassium salt to afford the corresponding 6-optionally substituted-2-(ethoxythiocarbonylthio)benzoic acid. The benzoic acid is then hydrolyzed to yield the 6- optionally substituted-2-mercaptobenzoic acid. The mercaptobenzoic acid is reacted with sodium hydride and an appropriately substituted heterocycle (for example 4,6-dimethoxy-2-methysulfonylpyrimidine) to yield the corresponding benzoic acid of Formula I (for example 6- optionally substituted-2-(4,6-dimethoxypyrimidin-2- ylthio)benzoic acid).

In an alternative route, the benzoic acid compound of Formula I in which Q is an optionally substituted alkyl or phenyl may also be prepared using a process involving a 2-ethoxycarbony1-3-(optionally substituted phenyl or alkyl) cyclohexen-5-one ester intermediate (intermediate Ila below) as described in F.M. Hauser et al., Synthesis. 10, 814 (1980). The following schema describes the synthetic route to intermediate Ila:

Intermediate Ila may be prepared by reacting ethyl acetoacetate with the appropriately 3-(optionally substituted alkyl or phenyl)propenal in the presence of a base, such as sodium alkoxide (for example sodium ethoxide), to form the corresponding keto-aldehyde intermediate Ia which, without isolation, is thereafter cyclized by acid catalysis to the corresponding

cyclohexenone intermediate Ila.

In the case of products having an oxygen bridge, the cyclohexenone intermediate Ila is then oxidized to the corresponding ethyl salicylate, for example ethyl 6- (optionally substituted phenyl or alkyl) salicylate, which is in turn hydrolyzed by basic catalysis to the corresponding salicylic acid (for example 6-(optionally substituted phenyl or alkyl) salicylic acid). The salicylic acid is then reacted with sodium hydride and the appropriately substituted heterocycle (for example 4,6-dimethoxy-2-methylsulfonylpyrimidine) to yield the corresponding benzoic acid of Formula I (for example 6- (optionally substituted phenyl or alkyl)-2-(4,6- dimethoxypyrimidin-2-yloxy)benzoic acid).

To prepare products having a sulfur or amino bridge, the cyclohexenone intermediate Ila is reacted with phosphorous pentasulfide or ammonia, respectively, to yield the corresponding thioketo or imino ester (for example 2-ethoxycarbonyl-3- (optionally substituted phenyl or alkyl) cyclohex-5-enthione or 2-ethoxycarbonyl- 3-(optionally substituted phenyl or

alkyl) cyclohexenimine, respectively). The thioketo or imino ester is in turn reacted with an oxidant such as, 2,3-dichloro-5,6-dicyano-1,4-benzoguinone and the like, to yield the corresponding benzoate or anthranilate (for example ethyl 2-mercapto-6-phenylbenzoate or ethyl 6- phenylanthranilate, respectively) . The benzoate or anthranilate is subsequently reacted with potassium hydroxide in the presence of 1,4,7,10,13,16- hexaoxacyclooctadecane to yield the corresponding benzoic acid of Formula I (for example 2-mercapto-6- (substituted phenyl or alkyl)benzoic acid or 6- (substituted phenyl or alkyl) anthranilic acid,

respectively).

In the 6-phenylbenzoic acids having an oxygen

bridge, the starting material may be 2- methoxybenzaldehyde. In compounds having a -S- or -NH- bridge, the starting material may be 2- methylthiobenzaldehyde or 2-nitrobenzaldehyde,

respectively. The appropriate 2-substituted benzaldehyde is reacted with aniline to yield the corresponding benzeneamine. The benzeneamine is then reacted with palladium(II) acetate to afford the

corresponding palladium(II) complex intermediate. The palladium(II) intermediate is reacted with triphenyl- phosphine and the appropriately Q substituted magnesium bromide to yield the corresponding 6-Q-2-(methoxy-, methylthio-, or nitro-substituted) benzaldehyde. If substituted with a methoxy or methylthio group, the benzaldehyde is reacted with boron tribromide or lithium iodide to cleave the methyl group thereby forming the corresponding salicylaldehyde or 2-mercaptobenzaldehyde, respectively. If substituted with a nitro group, the benzaldehyde is hydrogenated in the presence of

palladium on carbon to form the corresponding 2- aminobenzaldehyde. The salicylaldehyde, 2- mercaptobenzaldehyde or 2-aminobenzaldehyde is then reacted with potassium carbonate and the appropriately substituted 2-methylsulfonylpyrimidine or 2- methylsulfonyltriazine to yield the corresponding benzaldehyde having the formula

in which A, B, Q, R and R¹ are the same as indicated in Formula I. The benzaldehyde is in turn oxidized to afford the acid of Formula I.

The 6-phenylbenzoic acids, for example 6-phenyl-2- (4 ,6-dimethoxypyrimidin-2-yloxy)benzoic acid may be esterified by the reaction of the acid with a halogen containing moiety under basic conditions in an

appropriate solvent (triethylamine/acetonitrile or sodium bicarbonate/dimethylformamide).

In an alternate method, the benzoic acid ester may be formed by reacting the benzoyl halide with an alcohol or a phenol.

In another method, the benzoic acid is reacted with an alkylhaloformate such as methyl chloroformate in the presence of base to produce an intermediate mixed anhydride. The anhydride is then reacted with an alcohol or phenol to give an ester.

In an alternate method, the 6-phenylbenzoic acid may be esterified by the reaction of the acid with an alcohol or an optionally substituted phenol, for

example, 4-nitrophenol, and a dehydrating agent such as 1,3-dicyclohexlcarbodiimide or N,N'-carbonyldiimidazole in an appropriate solvent (methylene chloride).

In yet another alternative method, the 6- phenylbenzoic acid may be esterified with for example a lower alkyl alcohol by catalysis with acid.

Numerous other methods of esterification are well known in the art.

Alkylideneamino benzoates may be prepared as shown in Example 9 by the reaction of the 4-nitrophenyl benzoate with a ketone oxime in the presence of a base such as potassium carbonate.

EXAMPLE 1

Synthesis of 2-(4,6-dimethoxypyrimidin-2-yloxy)-

6-phenylbenzoic acid

(Compound 1)

Step A Synthesis of N-[(2-methoxyphenyl)methylene]- benzeneamine as an Intermediate

A stirred solution of 20.0 grams (0.146 mole) of 2- methoxybenzaldehyde and 13.7 grams (0.146 mole) of aniline was heated in 200 mL toluene at reflux while the jy-product water was collected in a Dean-Stark trap. The theoretical amount of water was collected in about four hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was dried under reduced pressure at 50°C for four hours, yielding 30.6 grams of N-[(2- methoxyphenyl)methylene]benzeneamine.

Step B Synthesis of bis(μ-acetato-O,O')bis[3-methoxy- 2-[(phenylimino)methyl]phenyl-C,N]dipalladium as an Intermediate

Under a nitrogen atmosphere, a stirred mixture of 9.3 grams (0.044 mole) of N-[(2-methoxyphenyl)- methylene]benzeneamine and 10.0 grams (0.044 mole) of palladium(II) acetate in 125 mL of glacial acetic acid was heated at reflux for one hour. The reaction mixture was then poured into 400 mL of ice-water to precipitate a solid. The resultant solid was collected by

filtration and dried under reduced pressure at 50°C for eight hours yielding 15.3 grams of bis (μ-acetato- O,O')bis[3-methoxy-2-[(phenylimino)methyl]phenyl- C,N]dipalladium. Step C Synthesis of 2-methoxy-6-phenylbenzaldehyde as an Intermediate

Under a dry nitrogen atmosphere, 21.0 grams (0.08 mole) of triphenylphosphine was added to a stirred suspension of 15.0 grams (0.02 mole) of bis (μ-acetato- O,O')bis[3-methoxy-2-[(phenylimino)methyl]phenyl- C,N]dipalladium in 200 mL of toluene. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 30 minutes. After this time 26.6 mL (0.08 mole) of phenylmagnesium bromide (3.0 molar in diethyl ether) was added via syringe during a five minute period. Upon completion of addition, the

reaction mixture was stirred for one hour, and 90 mL of aqueous 6N hydrochloric acid was added dropwise. Upon completion of addition, the reaction mixture was stirred for one hour, and then it was filtered. The filtrate was diluted with 200 mL of diethyl ether and was washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using heptane followed by 2:1

heptane/methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure yielding 1.4 grams of 2-methoxy-6-phenylbenzaldehyde.

Step D Synthesis of 6-phenylsalicylaldehyde as an

Intermediate

Under a nitrogen atmosphere, a stirred solution of 1.4 grams (0.0064 mole) of 2-methoxy-6-phenyl- benzaldehyde in 100 mL of methylene chloride was cooled to -78°C, and 9.6 mL (0.0096 mole) of boron tribromide

(1.0 molar in methylene chloride) was added via syringe. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. After this time the reaction mixture was diluted with 100 mL of methylene chloride and was washed with 200 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 - heptane/methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.6 gram of 6-phenylsalicylaldehyde. The nmr spectrum was consistent with the proposed structure.

Step E Synthesis of 4,6-dichloro-2-methylthio- pyrimidine as an Intermediate

Under a nitrogen atmosphere a stirred solution of 76.9 grams (0.49 mole) of 4,6-dihydroxy-2-methylthio- pyrimidine and 190 mL (2.04 moles) of phosphorus

oxychloride was heated at 95-100°C for two hours. After this time the reaction mixture was cooled to 5°C, and 250 mL of water was added dropwise during a 75 minute period. The mixture was warmed to 10°C, and an

additional 500 mL of water was added during a 15 minute period. The resultant solid was collected by filtration and was washed with two 100 mL portions of water. The solid was dried, yielding 84.7 grams of 4,6-dichloro-2- methylthiopyrimidine; m.p. 40.5-42.5°C. The reaction was repeated several times.

Step F Synthesis of 4, 6-dimethoxy-2-methylthiopyrimidine as an Intermediate

A stirred solution of 162.8 grams (0.832 mole) of 4, 6-dichloro-2-methylthiopyrimidine in 325 mL of

methanol was cooled to 15°C, and 419 mL (1.83 mole) of sodium methoxide (25% in methanol) was added dropwise at a rate to maintain the reaction mixture temperature below 20°C. Upon completion of the addition, which required 45 minutes, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 18 hours. After this time the reaction mixture was

concentrated under reduced pressure to a residual solid. The solid was dissolved in 850 mL of ethyl acetate. The solution was washed with one 500 mL portion and two 200 mL portions of water and then with one 200 mL portion of an aqueous solution saturated with sodium chloride. The aqueous washes were combined and extracted with one 350 mL portion of ethyl acetate. The ethyl acetate extract was then washed with one 150 mL portion of an aqueous solution saturated with sodium chloride. The ethyl acetate layers and extracts were combined and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 155.0 grams of 4,6-dimethoxy-2- methylthiopyrimidine, which solidified upon standing; m.p. 50-52°C.

Step G Synthesis of 4,6-dimethoxy-2-methylsulfonyl- pyrimidine as an Intermediate

A stirred solution of 143.6 grams (0.772 mole) of 4,6-dimethoxy-2-methylthiopyrimidine in 460 mL of tetrahydrofuran was cooled to 10-15°C, and a cloudy solution of 525.0 grams (0.849 mole) of 80%

monoperoxyphthalic acid, magnesium salt hexahydrate in 600 mL of methanol was added at a rate to maintain the reaction mixture temperature below 15°C. Upon

completion of the addition, which required one hour, the reaction mixture was cooled, and 500 mL of aqueous 1M sodium sulfite solution was added dropwise to destroy excess peroxides present in the reaction mixture. Upon completion of addition, the reaction mixture was stirred for 15 minutes and then was concentrated under reduced pressure to a residue. The residue was stirred in 2500 mL of ethyl acetate and 1500 mL of water. The layers were separated, and the aqueous layer was extracted with 450 mL of ethyl acetate. The ethyl acetate layers were combined and washed with one 500 mL portion of water, two 350 mL portions of aqueous 20% potassium carbonate, two 350 mL portions of water, and one 300 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 123.3 grams of 4,6-dimethoxy-2- methylsulfonylpyrimidine; m.p. 126-127.5°C. Step H Synthesis of 2-(4,6-dimethoxypyrimidin-2- yloxy)-6-phenylbenzaldehyde as an intermediate

Under a nitrogen atmosphere a stirred solution of 0.53 gram (0.0029 mole) of 6-phenylsalicylaldehyde (prepared in Steps A-D), 0.62 gram (0.0029 mole) of 4,6- dimethoxy-2-methylsulfonylpyrimidine (prepared in Steps E-G) and 0.36 gram (0.0029 mole) of potassium carbonate in 15 mL of dimethylformamide was heated at 85°C for four hours. After this time the reaction mixture was taken up in 100 mL of water and extracted with 50 mL of ethyl acetate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual gum. The residue was crystallized using carbon

tetrachloride/petroleum ether, yielding 0.75 gram of 2- (4,6-dimethoxypyrimidin-2-yloxy)-6-phenylbenzaldehyde.

Step I Synthesis of 2-(4,6-dimethoxypyrimidin-2- yloxy)-6-phenylbenzoic acid

(Compound 1)

To a stirred solution of 0.55 gram (0.0016 mole) of 2-(4,6-dimethoxypyrimidin-2-yloxy)-6-phenylbenzaldehyde in 15 mL of acetone was added a solution of 0.26 gram (0.0016 mole) of potassium permanganate and 0.22 gram (0.0016 mole) of sodium phosphate, dibasic heptahydrate in 10 mL of water. Upon completion of addition, the reaction mixture was stirred for six hours. The reaction mixture was then treated with 1 mL of an aqueous solution saturated with sodium thiosulfate and was filtered through diatomaceous earth. The filtrate was refiltered and was concentrated under reduced pressure to remove the acetone. The concentrate was diluted with 50 mL of water and was extracted with two 50 mL portions of ethyl acetate. The aqueous layer was then acidified to pH 3 using aqueous 10% hydrochloric acid and reextracted with three 75 mL portions of ethyl acetate. The combined extracts were concentrated under reduced pressure to a residue. The residue was

crystallized with carbon tetrachloride and petroleum ether, yielding in two crops 0.43 gram of 2-(4,6- dimethoxypyrimidin-2-yloxy) -6-phenylbenzoic acid,

Compound 1 of Table 1. The nmr spectrum was consistent with the proposed structure.

EXAMPLE 2

Synthesis of 2-(4,6-dimethoxypyrimidin-2-yloxy)-

6- (thien-2-yl)benzoic Acid

(Compound 1a)

Step A Synthesis of (thien-2-yl)magnesium bromide as an Intermediate

Under a nitrogen atmosphere, a few mL of dry diethyl ether was placed in the appropriate reaction vessel with 1.8 grams (0.072 mole) of magnesium turnings. A few mL of a solution of 11.7 grams (0.072 mole) of 2- bromothiophene in 50 mL of dry diethyl ether was then added to the reaction vessel. A crystal of iodine was then added to initiate the formation of the Grignard reagent. After the reaction was initiated, the

remainder of the 2-bromothiophene solution was added dropwise to the stirred reaction mixture at a rate to promote gentle reflux. Upon completion of addition, refluxing of the reaction mixture was continued for an additional 55 minutes. The so-prepared ethereal

solution of (thien-2-yl)magnesium bromide was used immediately without isolation. Step B Synthesis of 2-methoxy-6-(thien-2-yl)- benzaldehyde as an Intermediate

Under a nitrogen atmosphere a solution of 13.5 grams (0.018 mole) of bis(μ-acetato-O,O')bis[3-methoxy-2- [(phenylimino)methyl]phenyl-C,N]dipalladium (prepared as in Example 1, Steps A and B) and 18.9 grams (0.072 mole) of triphenylphosphine in 250 mL of dry toluene was stirred for about 1 hour, and the ethereal solution of (thien-2-yl)magnesium bromide was added via syringe during a 10 minute period. Upon completion of addition, the reaction mixture was stirred for about 18 hours, and then 90 mL of aqueous 6N hydrochloric acid was added. The reaction mixture was then filtered through

diatomaceous earth. The organic layer was separated and was washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 50% heptane in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.0 grams of 2-methoxy-6-(thien-2- yl)benzaldehyde. The nmr spectrum was consistent with the proposed structure. Step C Synthesis of 6-(thien-2-yl) salicylaldehyde as an Intermediate

Under a nitrogen atmosphere a stirred solution of 0.3 gram (0.001) of 2-methoxy-6-(thien-2-yl)benzaldehyde and 0.3 gram (0.002 mole) of anhydrous lithium iodide in 10 mL of 2,4, 6-trimethylpyridine was heated at reflux for 20 minutes. After this time an aliquot of the reaction mixture was acidified with aqueous 6N

hydrochloric acid. The aliquot was extracted with diethyl ether, and the extract was subjected to gas chromatographic analysis. The analysis indicated that the reaction was complete. The entire reaction mixture was acidified with aqueous 6N hydrochloric acid.

A second reaction mixture containing the reaction of 1.7 grams (0.0078 mole) of 2-methoxy-6-(thien-2- yl)benzaldehyde and 1.7 grams (0.013 mole) of anhydrous lithium iodide, in 10 mL of 2,4,6-trimethylpyridine was also acidified with aqueous 6N hydrochloric acid. The two acidified reaction mixtures were combined, and the combination was extracted with diethyl ether and then with ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 50% heptane in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.9 gram of 6-(thien-2-yl) salicylaldehyde. The nmr spectrum was consistent with the proposed structure.

Step D Synthesis of 2-(4,6-dimethoxypyrimidin-2- yloxy)-6-(thien-2-yl)benzaldehyde as an Intermediate Under a nitrogen atmosphere a stirred solution of 0.7 grams (0.003 mole) of 6-(thien-2-yl)salicylaldehyde, 0.5 gram (0.004 mole) of potassium carbonate, and 0.7 gram (0.003 mole) of 4,6-dimethoxy-2- methylsulfonylpyrimidine in 10 mL of dimethylformamide was heated at 80°C for 2 hours. The reaction mixture was taken up in water and an aqueous solution saturated with sodium chloride, and then it was extracted with two portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was evacuated under high vacuum, causing it to solidify. The solid was triturated with cold

petroleum ether. The solid was collected by filtration, yielding 0.9 gram of 2-(4,6-dimethoxypyrimidin-2-yloxy)- 6-(thien-2-yl)benzaldehyde; m.p. 97.5-101°C. The nmr spectrum was consistent with the proposed structure.

Step E Synthesis of 2-(4,6-dimethoxypyrimidin-2- yloxy)-6-(thien-2-yl)benzoic acid

(Compound 1a)

A stirred solution of 0.12 gram (0.0004 mole) of 2- (4,6-dimethoxypyrimidin-2-yloxy)-6-(thien-2- yl)benzaldehyde in 1.2 mL of acetone was cooled in an ice-salt bath, and 1.2 mL of a mixture of aqueous 0.3M potassium permanganate and aqueous 0.15M sodium

phosphate, dibasic heptahydrate was added. Upon

completion of addition, the reaction mixture was stirred while being cooled in the ice-salt bath for 1 hour.

Thin layer chromatographic analysis of the reaction mixture indicated that the reaction was not proceeding well. The ice-salt bath was removed, and the reaction mixture was allowed to warm to ambient temperature where it stirred for 4.75 hours. After this time the purple color was dissipated from the reaction mixture by the careful dropwise addition of an aqueous solution

saturated with sodium thiosulfate.

A second reaction mixture containing the reaction of 0.5 grams (0.002 mole) of 2-(4,6-dimethoxypyrimidin-2- yloxy)-6-(thien-2-yl)benzaldehyde and 5.4 mL of a mixture of aqueous 0.3M potassium permanganate and aqueous 0.15M sodium phosphate, dibasic heptahydrate in 10 mL of acetone was also treated with an aqueous solution saturated with sodium thiosulfate.

The two reaction mixtures were combined and the combination was filtered through diatomaceous earth.

The filtrate was concentrated under reduced pressure to remove volatile material. The aqueous concentrate was washed with diethyl ether, and then it was acidified to pH 2 with aqueous 6N hydrochloric acid. The mixture was extracted with three portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.6 gram of 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-(thien-2-yl) benzoic acid; m.p. 139-140°C, Compound la of Table 1A. The nmr spectrum was consistent with the proposed structure. EXAMPLE 3

Synthesis of 2-(4,6-dimethoxypyrimidin-2-ylthio)- 6-phenylbenzoic acid

Step A Synthesis of N-[2-methylthiophenyl)methylene]- benzeneamine as an Intermediate

A stirred solution of 22.2 grams (0.146 mole) of 2- methylthiobenzaldehyde and 13.7 grams (0.146 mole) of aniline is heated at reflux while the by-product water is collected in a Dean-Stark trap. After collection of the theoretical amount of water, the reaction mixture is concentrated under reduced pressure to a residue. The residue is dried under reduced pressure at 50°C,

yielding N-[(2-methylthiophenyl)methylene]benzeneamine.

Step B Synthesis of bis(μ-acetato-O,O')bis[3- methylthio-2-[(phenylimino)methyl]phenyl-C,N]- dipalladium as an Intermediate Under a nitrogen atmosphere, a stirred mixture of 10.0 grams (0.044 mole) of N-[(2-methylthiophenyl)- methylene]benzeneamine and 10.0 grams (0.044 mole) of palladium(II) acetate in 125 mL of glacial acetic acid is heated at reflux for one hour. After this time the reaction mixture is poured into ice-water. The material is collected and dried under reduced pressure at 50°C, yielding bis (μ-acetato-O,O')bis[3-methylthio-2- [(phenylimino)methyl]phenyl-C,N]dipalladium. Step C Synthesis of 2-methylthio-6-phenylbenzaldehyde as an Intermediate

Under a dry nitrogen atmosphere, 21.0 grams (0.08 mole) of triphenylphosphine is added to a stirred suspension of 15.7 grams (0.02 mole) of bis (μ-acetato- O,O')bis[3-methylthio-2-[(phenylimino)methyl]phenyl- C,N]dipalladium in 200 mL of toluene. Upon completion of addition, the reaction mixture is stirred at ambient temperature for 30 minutes. After this time 26.6 mL (0.08 mole) of phenylmagnesium bromide (3.0 molar in diethyl ether) is added via syringe during a five minute period. Upon completion of addition, the reaction mixture is stirred for one hour, and 90 mL of aqueous 6N hydrochloric acid is added dropwise. Upon completion of addition, the reaction mixture is stirred for one hour and then is filtered. The filtrate is diluted with 200 mL of diethyl ether and is washed with an aqueous solution saturated with sodium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column

chromatography on silica gel. Elution is accomplished using heptane followed by 2:1 heptane/methylene

chloride. The appropriate fractions are combined and concentrated under reduced pressure, yielding 2- methylthio-6-phenylbenzaldehyde.

Step D Synthesis of 2-mercapto-6-phenylbenzaldehyde as an Intermediate

Under a nitrogen atmosphere, a solution of 1.5 grams (0.0064 mole) of 2-methylthio-6-phenylbenzaldehyde in 10 mL of 2,4,6-trimethylpyridine is stirred, and 1.7 grams (0.0128 mole) of lithium iodide is added. Upon

completion of addition the reaction mixture is warmed to

100°C where it is stirred for 3 hours. The cooled reaction mixture is acidified to a pH of 2 with

concentrated hydrochloric acid, and then is extracted with two 150 mL portions of methylene chloride. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure yielding 2-mercapto-6-phenylbenzaldehyde.

Step E Synthesis of 2-(4,6-dimethoxypyrimidin-2-yl- thio)-6-phenylbenzaldehyde as an Intermediate

Under a nitrogen atmosphere a stirred solution of 0.57 gram (0.0029 mole) of 2-mercapto-6-phenyl- benzaldehyde (prepared in Steps A-D), 0.62 gram (0.0029 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (prepared in Steps E-G of Example 1) and 0.36 gram

(0.0029 mole) of potassium carbonate in 15 mL of dimethylformamide is heated at 85°C for four hours.

After this time the reaction mixture is taken up in 100 mL of water and extracted with 50 mL of ethyl acetate. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-(4,6-dimethoxypyrimidin-2-ylthio)- 6-phenylbenzaldehyde.

Step F Synthesis of 2-(4,6-dimethoxypyrimidin-2- ylthio)-6-phenylbenzoic acid

To a stirred solution of 0.56 gram (0.0016 mole) of 2-(4,6-dimethoxypyrimidin-2-ylthio)-6-phenylbenzaldehyde in 15 mL of acetone is added a solution of 0.26 gram (0.0016 mole) of potassium permanganate and 0.22 gram (0.0016 mole) of sodium phosphate, dibasic heptahydrate in 10 mL of water. Upon completion of addition, the reaction mixture is stirred for six hours. The reaction mixture is then treated with 1 mL of an aqueous solution saturated with sodium thiosulfate and is filtered through diatomaceous earth. The filtrate is refiltered and is concentrated under reduced pressure to remove the acetone. The concentrate is diluted with 50 mL of water and is extracted with two 50 mL portions of ethyl acetate. The aqueous layer is then acidified to pH 3 using aqueous 10% hydrochloric acid and reextracted with three 75 mL portions of ethyl acetate. The combined extracts are concentrated under reduced pressure, yielding 2-(4,6-dimethoxypyrimidin-2-ylthio)-6- phenylbenzoic acid. EXAMPLE 4

Synthesis of 6-phenyl-2-(4,6-dimethoxypyrimidin- 2-yloxy)benzoic acid Step A Synthesis of 2-ethoxycarbonyl-3-phenylcyclohex- 5-enone as an intermediate

Under a nitrogen atmosphere, 0.1 gram (0.004 mole) of sodium metal was reacted in 40 mL of ethanol. The solution was stirred, and 13.0 grams (0.100 mole) of ethyl acetoacetate was added. The reaction mixture was cooled in an ice bath, and 13.2 grams (0.100 mole) of trans-cinnamaldehyde in 10 mL of ethanol was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. After this time the reaction mixture was saturated with gaseous hydrochloric acid and then was allowed to stand for about 65 hours. The reaction mixture was

concentrated under reduced pressure to yield

2-ethoxycarbonyl-3-phenylcyclohex-5-enone. A 100% yield (24.4 grams) of product was assumed.

The reaction was repeated replacing the sodium metal with ethyl acetoacetate, sodium salt. Thus, 12.6 grams (0.097 mole) of ethyl acetoacetate, 0.5 gram (0.003 mole) of ethyl acetoacetate, sodium salt and 13.2 grams (0.100 mole) of trans-cinnamaldehyde in 50 mL of ethanol were reacted. A 100% yield (24.4 grams) of 2- ethoxycarbonyl-3-phenylcyclohex-5-enone was assumed.

Step B Synthesis of ethyl 6-phenylsalicylate as an

intermediate

Under a nitrogen atmosphere, a stirred solution of 24.4 grams (0.100 mole) of crude 2-ethoxycarbonyl-3- phenylcyclohex-5-enone in 50mL of carbon tetrachloride was cooled in an ice bath, and a solution of 16.1 grams (0.100 mole) of bromine in 50 mL of acetic acid was added dropwise. Upon completion of addition, the reaction mixture was stirred at the ice-bath temperature for 30 minutes. After this time the reaction mixture was warmed to reflux where it was stirred for about 21 hours. The reaction mixture was cooled and then was stirred with 80 mL of methylene chloride and 80 mL of water. The layers were separated, and the organic layer was washed with two portions of water and with one portion of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with sodium sulfate and magnesium sulfate and then was filtered.

The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column

chromatography on silica gel. Elution was accomplished using 2:1-heptane and methylene chloride. The

appropriate fractions were combined and concentrated under reduced pressure to yield 7.1 grams of ethyl 6- phenylsalicylate. The nmr spectrum was consistent with the proposed structure. Step C Synthesis of 6-phenylsalicylic acid as an

intermediate

To a stirred solution of 3.3 grams (0.014 mole) of ethyl 6-phenylsalicylate in 30 mL of ethanol was added a catalytic amount of 1,4,7,10,13,166hexaoxacyclo- octadecane. This was followed by the addition of a solution of 2.0 grams (0.030 mole) of 85% potassium hydroxide in 15 mL of water. Upon completion of addition, the reaction mixture was warmed to reflux where it was stirred for 4 hours. The reaction mixture was allowed to cool to ambient temperature where it stood for about 18 hours. After this time the reaction mixture was again warmed to reflux where it stirred for 4 hours. Thin layer chromatographic analysis of the reaction mixture indicated the reaction had not gone to completion. An additional 0.3 gram of 85% potassium hydroxide was added to the reaction mixture and the heating at reflux was continued for another 3 hours. After this time the reaction mixture was cooled, and volatile materials were removed under reduced pressure. The aqueous concentrate was washed with two portions of diethyl ether. The combined ether washes were

backwashed with water. The water washes and the aqueous concentrate were combined, and the combination was acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted with three portions of ethyl acetate. The combined extracts were dried with

magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in hot ethanol, and the solution was treated with decolorizing carbon. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to a residue. The residue was recrystallized from diethyl ether and hexane to yield 6-phenylsalicylic acid, m.p. 143-146°.

The filtrate from the recrystallization was concentrated under reduced pressure to a residual solid. The residue was combined with the 6-phenylsalicylic acid, m.p. 143- 146°C, yielding 2.8 grams of this material.

Step D Synthesis of 6-phenyl-2-(4,6- dimethoxypyrimidin-2-yloxy)benzoic acid

Under a nitrogen atmosphere, a stirred mixture of 0.25 gram (0.0052 mole) of 50-60% sodium hydride (in mineral oil) in 60 mL of tetrahydrofuran was cooled in an ice bath and 0.54 gram (0.0025 mole) of 6- phenylsalicylic acid was added. The reaction mixture was stirred for about 5 minutes and 0.55 gram (0.0025 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added. Upon completion of addition the ice bath was removed and the reaction mixture was stirred fro about 50 minutes. Thin layer chromatographic analysis of the reaction mixture at this time indicated the reaction was greater than 90% complete.

The above reaction mixture was combined with another reaction mixture consisting of the reaction of 1.73 grams (0.0079 mole) of 6-phenylsalicylic acid, 1.70 grams (0.0079 mole) of 4,6-dimethoxy-2- methylsulfonylpyrimidine and 0.78 gram (0.016 mole) of 50-60% sodium hydride in mineral dissolved in 120 mL of tetrahydrofuran. The combination was taken up in water and was washed with diethyl ether. The aqueous layer was acidified to a pH of 2 with aqueous normal

hydrochloric acid. The mixture was extracted with three portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a foamy residue. The residue was dissolved in diethyl ether and the solution was extracted with two portions of an aqueous solution saturated with sodium bicarbonate. The combined extracts were acidified to a pH of 2 with aqueous 6N hydrochloric acid. The mixture was then extracted with three portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was recrystallized with methylene chloride and hexane, yielding 1.74 grams of 6-phenyl-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid. The nmr spectrum was consistent with the proposed structure. EXAMPLE 5

Synthesis of 2-(4,6-dimethoxypyrimidin-2-yloxy)-

6-(4-nitrophenyl)benzoic acid

(Compound 27)

Step A Synthesis of 2-ethoxycarbonyl-3-(4- nitrophenyl)cyclo-5-enone as an intermediate

A stirred mixture of 6.8 grams (0.052 mole) of ethyl acetoacetate and 0.24 gram ( 0.002 mole) of the sodium salt of ethyl acetoacetate in a small amount of ethanol was cooled in an ice-bath, and a suspension of 9.5 grams (0.054 mole) of 4-nitrocinnamaldehyde in 100 mL of ethanol was added during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred under a nitrogen atmosphere for about 18 hours. The stirred reaction mixture was cooled in an ice-bath and was saturated with hydrogen chloride gas. After this time the reaction mixture was allowed to warm to ambient temperature where it stood for about 60 hours. The reaction mixture was concentrated under reduced

pressure, yielding about 15.5 grams of 2-ethoxycarbonyl- 3-(4-nitrophenyl)cyclohex-5-enone. The product was used without further purification.

Step B Synthesis of ethyl 6-(4-nitrophenyl)salicylate as an intermediate A stirred solution of 15.5 grams (0.054 mole) of 2- ethoxycarbonyl-3-(4-nitrophenyl)cyclohex-5-enone in 40 mL of carbon tetrachloride was cooled in an ice bath, and a solution of 2.8 mL (0.054 mole) of bromine in 40 mL of acetic acid was added in one portion. Upon completion of addition, the reaction mixture was cooled for an additional 40 minutes, and then it was warmed to reflux where it was stirred for about 18 hours. After this time the reaction mixture was cooled to ambient temperature where it was stirred with 45 mL of water, an additional 45 mL of carbon tetrachloride, and 45 mL of methylene chloride. The organic layer was separated was washed with two portions of water and one portion of an aqueous solution saturated with sodium bicarbonate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 16.4 grams of ethyl 6- (4-nitrophenyl) salicylate.

Note: Steps A and B of this Example were prepared by the method of Heuser and Pogany Step C Synthesis of 6-(4-nitrophenyl)salicylic acid as an intermediate

To a warm, stirred solution of 6.9 grams (0.029 mole) of ethyl 6-(4-nitrophenyl) salicylate in 100 mL of ethanol was added a solution of 4.8 grams (0.072 mole) of .85% potassium hydroxide in 50 mL of water. Upon completion of addition, the reaction mixture was warmed to reflux where it was stirred for about 16 hours.

After this time the ethanol was removed under reduced pressure. The aqueous concentrate was washed with diethyl ether and then acidified to pH 1 with aqueous 6N hydrochloric acid. The mixture was extracted with one portion of ethyl acetate. The separation of the aqueous and the organic layers was incomplete. The mixture was passed through diatomaceous earth, which resulted in the separation of the layers. The organic layer was removed, and the aqueous layer was extracted with two additional portions of ethyl acetate. The combined extracts were dried with magnesium sulfate, and the mixture was filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was recrystallized from diethyl ether/pentane, yielding 4.2 grams of 6-(4-nitrophenyl) salicylic acid; m.p. 205- 208ºC. The nmr spectrum was consistent with the proposed structure.

Step D Synthesis of 2-(4,6-dimethoxypyrimidin-2- yloxy)-6-(4-nitrophenyl) benzoic acid (Compound 27)

Under a nitrogen atmosphere, a suspension of 1.4 grams (0.028 mole) of 60% sodium hydride (in mineral oil) in 200 mL of tetrahydrofuran was stirred, and 3.7 grams (0.014 mole) of 6-(4-nitrophenyl) salicylic acid in 20 mL of tetrahydrofuran was added. Upon completion of addition, the reaction was stirred for five minutes, then it was cooled in an ice-water bath, and a solution of 3.2 grams (0.015 mole) of 4,6-dimethoxy-2- methylsulfonylpyrimidine (prepared in Example 1, Steps E-G) in 5 mL of tetrahydrofuran was added. Upon

completion of addition, the reaction mixture was allowed to slowly warm to ambient temperature as it stirred during about an 18 hour period. Thin layer

chromatographic (TLC) analysis of the reaction mixture indicated the presence of a small amount of the

intermediate salicylic acid. An additional 0.25 gram (0.001 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added, followed by 15 mL of tetrahydrofuran. The reaction mixture was then warmed to 35°C where it was stirred for about two hours. After this time TLC analysis of the reaction mixture still indicated the presence of the intermediate salicylic acid. A

catalytic amount of 1,4,7,10,13-pentaoxacyclopentadecane (15-crown-5) was added to the reaction mixture, and heating at 35ºC was continued for about three hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in water and washed with two portions of ethyl acetate. The aqueous layer was acidified to pH 1 with concentrated hydrochloride acid, and the mixture was extracted with two portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The solid was triturated with ethanol and then was washed with pentane. The still impure solid was then recrystallized from ethanol, yielding 1.5 grams of 2-(4,6-dimethoxypyrimidin-2- yloxy) -6-(4-nitrophenyl)benzoic acid; m.p. 150.5°C. The nmr spectrum was consistent with the proposed structure.

EXAMPLE 6

Synthesis of 2-(4,6-dimethoxypyrimidin-2-yloxy)-

6-(2,4,6-trimethylphenyl)benzoic acid

(Compound 49)

Step A Synthesis of 2-(2,6-difluorophenyl)-4,5- dihydro-4,4-dimethyloxazole as an intermediate

A stirred solution of 25.2 grams (0.283 mole) of 2- amino-2-methyl-1-propanol in 83 mL of anhydrous

methylene chloride was cooled in an ice-water bath, and a solution of 25.0 grams (0.142 mole) of 2,6- difluorobenzyl chloride in 83 mL of anhydrous methylene chloride was added dropwise at a rate such that the reaction mixture temperature did not exceed 15ºC. Upon completion of addition, which required 30 minutes, the reaction mixture was allowed to warm to ambient

temperature where it was stirred for about 18 hours. After this time the reaction mixture was washed with water and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 31.2 grams of white solid. The solid was stirred, and 55.6 grams (0.467 mole) of thionyl chloride was added dropwise. External heating was required to promote the formation of a homogeneous mixture. The mixture was stirred for 45 minutes and then was poured into 150 mL of vigorously stirred diethyl ether. The diethyl ether was decanted from the resultant solid. The solid was then dissolved in water, and the solution was neutralized with aqueous 10% sodium hydroxide solution. The mixture was

extracted with diethyl ether. The ether extract was washed with an aqueous solution saturated with sodium chloride and then was dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 25.3 grams of 2-(2,6- difluorophenyl)-4,5-dihydro-4,4-dimethyloxazole. Step B Synthesis of 2-[2-fluoro-6-(2,4,6- trimethylphenyl) phenyl]-4,5-dihydro-4,4- dimethyloxazole as an intermediate

Under a nitrogen atmosphere a solution of 100 mL (0.10 mole) of 2-mesitylmagnesium bromide (a 1.0M solution in tetrahydrofuran) in 200 mL of

tetrahydrofuran was stirred, and a solution of 17.6 grams (0.08 mole) of 2-(2,6-difluorophenyl)-4,5-dihydro- 4,4-dimethyloxazole in 200 mL of tetrahydrofuran was added dropwise during a 15 minute period. Upon

completion of addition, the reaction mixture was heated at reflux for two days. After this time the reaction mixture was poured into water. The mixture was

extracted with diethyl ether, and the extract was washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 26.0 grams of 2-[2-fluoro-6-(2,4,6- trimethylphenyl)phenyl]-4,5-dihydro-4,4-dimethyloxazole. The nmr spectrum was consistent with the proposed structure.

Step C Synthesis of 2-[2-fluoro-6-(2,4,6- trimethylphenyl)phenyl]-4,5-dihydro-3,4,4- trimethyloxazolium iodide as an intermediate

A stirred solution of 10.0 grams (0.032 mole) of 2- [2-fluoro-6-(2,4,6-trimethylphenyl)phenyl]-4,5-dihydro- 4,4-dimethyloxazole and 36.5 grams (0.257 mole) of methyl iodide in 65 mL of nitromethane was heated at reflux for about 26 hours. After this time the reaction mixture was concentrated under reduced pressure to about 15 mL and then was poured with stirring into 200 mL of cold diethyl ether. The resultant solid was collected by filtration, washed with diethyl ether, and dried, yielding 12.6 grams of 2-[2-fluoro-6-(2,4,6- trimethylphenyl)phenyl]-4,5-dihydro-3,4,4- trimethyloxazolium iodide. The nmr spectrum was

consistent with the proposed structure.

Step D Synthesis of 2-fluoro-6-(2,4,6- trimethylphenyl)benzaldehyde as an intermediate A 9.0 gram (0.02 mole) sample of 2-[2-fluoro-6- (2,4, 6-trimethylphenyl)phenyl]-4,5-dihydro-3,4,4- trimethyloxazolium iodide was completely dissolved in 52 mL of ethanol and, with stirring, 1.1 grams (0.03 mole) of sodium borohydride was cautiously added during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at ambient temperature for two hours. After this time 166 mL of aqueous 3N hydrochloric acid was slowly added. Upon completion of addition, the reaction mixture was warmed to 110° C where it was stirred for two hours. The reaction mixture was cooled, diluted with water, and then was extracted with diethyl ether. The extract was washed with water and then with an aqueous solution saturated with sodium chloride. The extract was then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.7 grams of 2-fluoro- 6-(2,4,6-trimethylphenyl)benzaldehyde. The nmr spectrum was consistent with the proposed structure. Step E Synthesis of 6-(2,4,6- trimethylphenyl) salicylaldehyde as

an intermediate

A 3.0 gram (0.012 mole) sample of 2-fluoro-6-(2,4,6- trimethylphenyl)benzaldehyde was completely dissolved in 30 mL of tetrahydrofuran and, with stirring, 0.4 gram (catalyst) of tetrabutylammonium bromide was added. The reaction mixture was then cooled in an ice-water bath, and 1.0 gram (0.025 mole) of sodium hydroxide was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 24 hours. The reaction mixture was then poured into water. The mixture was acidified with concentrated hydrochloric acid and then was extracted with diethyl ether. The ether extract was washed with water and then with an aqueous solution saturated with sodium chloride. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column

chromatography using silica gel. Elution was accomplished using 5:95 - ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.4 grams of 6-(2,4,6- trimethylphenyl) salicylaldehyde. The nmr spectrum was consistent with the proposed structure. The reaction was repeated a second time to provide sufficient

material for the subsequent reaction.

Step F Synthesis of 2-(4,6-dimethoxypyrimidin-2- yloxy)-6-(2,4,6-trimethylphenyl)benzaldehyde as an intermediate

This compound was prepared in a manner analogous to that of Example 1, Step H, using 1.3 grams (0.005 mole) of 6-(2,4,6-trimethylphenyl)-salicylaldehyde, 1.2 grams (0.005 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (prepared in Example 1, Steps E-G), and 0.8 gram (0.006 mole) of potassium carbonate in 8.5 mL of

dimethylformamide. The crude product was triturated with diethyl ether, and then was subjected to column chromatography using silica gel. Elution was

accomplished using 1:2 - ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.4 grams of 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-(2,4,6- trimethylphenyl)benzaldehyde; m.p. 146-147ºC. The nmr spectrum was consistent with the proposed structure.

Step G Synthesis of 2-(4,6-dimethoxypyrimidin-2- yloxy)-6-(2,4,6-trimethylphenyl)benzoic acid

(Compound 49)

This compound was prepared in a manner analogous to that of Example 1, Step I, using 1.3 grams (0.003 mole) of 2-(4,6-dimethoxypyrimidin-2-yloxy)-6-(2,4,6- trimethylphenyl)benzaldehyde, 0.8 gram (0.005 mole) of sodium phosphate, dibasic heptahydrate in 22.5 mL of water and 39 mL of acetone. The reaction mixture was filtered through diatomaceous earth. The filtrate was acidified with concentrated hydrochloric acid and then it was extracted with methylene chloride. The extract was washed with an aqueous solution saturated with sodium chloride, and then it was dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual solid. The solid was subjected to column chromatography using silica gel. Elution was accomplished using first 1:3 - ethyl acetate in hexane, and then 2:9 - methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of 2-(4,6-dimethoxypyrimidin-2-yloxy)- 6-(2,4,6-trimethylphenyl)benzoic acid. The nmr spectrum was consistent with the proposed structure. EXAMPLE 7

Synthesis of 2-(4,6-dimethoxypyrimidin-2-yloxy)-

6-(pyridin-4-yl)benzoic acid

(Compound 36) Step A Synthesis of 3-(pyridin-4-yl)propenal as an

intermediate

Under a nitrogen atmosphere a solution of 20.0 grams (0.187 mole) of 4-pyridinecarboxaldehyde and 56.8 grams (0.187 mole) of formylmethylenetriphenylphosphorane in 350 mL of toluene was heated at reflux for about one hour. After this time the reaction mixture was cooled and concentrated under reduced pressure. The

concentrate was dissolved in diethyl ether and the solution was placed in a freezer. When cold, the solution was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was evacuated under high pressure, yielding 28.7 grams (theoretical yield 24.9 grams) of material. The concentrate was stored in a freezer for about 18 hours and then was redissolved in diethyl ether. Pentane was added to the solution until an oily material dropped out of the solution. The mixture was cooled in a dry ice-acetone bath and was stirred. The resultant solid was collected by filtration, yielding 22.3 grams of 3-(pyridin-4- yl)propenal; m.p. 29ºC. The nmr spectrum was

consistent with the proposed structure. Step B Synthesis of 2-ethoxycarbonyl-3-(pyridin-4- yl)cyclohex-5-enone as an intermediate

This compound was prepared in a manner analogous to that of Example 5, Step A, using 21.8 grams (0.163 mole) of 3-(pyridin-4-yl)propenal, 20.6 grams (0.158 mole) of ethyl acetoacetate, 0.8 gram (0.005 mole) of the sodium salt of ethyl acetoacetate in 60 mL of ethanol.

Following treatment with hydrogen chloride gas, the reaction mixture was allowed to stir at ambient

temperature for about 18 hours. The yield of 2- ethoxycarbonyl-3-(pyridin-4-yl) cyclohex-5-enone was about 38.6 grams. The product was used without further purification. Step C Synthesis of ethyl 6-(pyridin-4-yl)salicylate as an intermediate

This compound was prepared in a manner analogous to that of Example 5, Step B, using 38.6 grams (0.158 mole) of 2-ethoxycarbonyl-3-(pyridin-4-yl)cyclohex-5-enone, 8.5 mL (0.160 mole) of bromine, 110 mL of acetic acid and 110 mL of carbon tetrachloride. The reaction mixture residue was subjected to column chromatography using silica gel. Elution was accomplished first with methylene chloride, and then with 5% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to a residue. The residue was triturated with hot methanol, and the resultant solid was collected by filtration, yielding 4.8 grams of ethyl 6-(pyridin-4-yl) salicylate; m.p. 169.5-172ºC. The nmr spectrum was consistent with the proposed structure.

Step D Synthesis of phenylmethyl 6-(pyridin-4- yl) salicylate as an intermediate

Under a nitrogen atmosphere a stirred mixture of 1.4 grams (0.006 mole) of ethyl 6- (pyridin-4-yl) salicylate, 6.2 grams (0.057 mole) of phenylmethanol, 0.2 gram

(0.001 mole) of titanium (IV) isopropoxide and 10 grams of 4A molecular sieves (beads) in 100 mL of

tetrahydrofuran was heated at reflux for about 30 hours. After this time the reaction mixture was filtered through diatomaceous earth. The filter cake was washed with tetrahydrofuran, and the combined wash and filtrate were concentrated under reduced pressure to a residual oil. The residual oil of a previous run (0.002 mole of the salicylate) of this reaction was combined with the present residual oil, and the combination was subjected to column chromatography using silica gel. Elution was accomplished using ethyl acetate in hexane at

concentrations varying from 20% to 100% ethyl acetate. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.5 grams of

phenylmethyl 6-(pyridin-4-yl) salicylate; m.p. 170- 172.5ºC. The nmr spectrum was consistent with the proposed structure.

Step E Synthesis of phenylmethyl 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-(pyridin-4- yl)benzoate as an intermediate

(Compound 106)

Under a nitrogen atmosphere a mixture of 0.10 gram (0.002 mole) of 60% sodium hydride (in mineral oil) in 8 mL of dimethylformamide was stirred, and 0.65 gram

(0.002 mole) of phenylmethyl 6-(pyridin-4-yl)salicylate in 4 mL of dimethylformamide was added. The reaction mixture was stirred for about five minutes, and a solution of 0.49 gram (0.002 mole) of 4,6-dimethoxy-2- methylsulfonylpyrimidine (prepared in Example 1, Steps E-G) in 3 mL of dimethylformamide was added. After this time the reaction mixture was warmed to 80ºC where it was stirred for 1.5 hours. The reaction mixture was cooled, and water was added to it. The mixture was extracted with three portions of ethyl acetate. The combined extracts were washed with water and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was crystallized with diethyl ether. The resultant solid was collected by filtration and was washed with hexane. The solid was dried, yielding 0.69 gram of phenylmethyl 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-(pyridin-4-yl)benzoate; m.p. 115-117ºC. The nmr spectrum was consistent with the proposed structure.

Step F Synthesis of 2-(4,6-dimethoxypyrimidin-2- yloxy)-6-(pyridin-4-yl)benzoic acid

(Compound 36) Under a nitrogen atmosphere 0.04 gram (catalyst) of 10% palladium on charcoal in 30 mL of methanol was stirred, and 0.42 gram (0.001 mole) of phenylmethyl 2- (4,6-dimethoxypyrimidin-2-yloxy)-6-(pyridin-4- yl) benzoate was added. The reaction vessel was

evacuated and refilled with nitrogen several times.

Upon completion of the final evacuation, a hydrogenfilled balloon was attached to a syringe, and the syringe was inserted through a septum placed over a neck of the reaction vessel. The reaction mixture was stirred under the hydrogen atmosphere for about one hour. A sample of the reaction mixture was subjected to thin layer chromatography, which indicated that the reaction had gone to completion. The reaction vessel was evacuated and filled with nitrogen several times. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to a residual oil. The oil was crystallized with carbon tetrachloride, and the solid was triturated with carbon tetrachloride and hexane. The solid was collected by filtration and dried, yielding 0.11 gram of 2-(4,6-dimethoxypyrimidin-2-yloxy)-6-(pyridin-4- yl)benzoic acid. The nmr spectrum was consistent with the proposed structure.

EXAMPLE 8

Synthesis of 2-(4,6-dimethoxy-1,3,5-triazin-

2-yloxy)-6-(4-chlorophenyl)benzoic acid

(Compound 113)

Step A Synthesis of 4-chlorocinnamaldehyde as an

intermediate

A stirred solution of 20.0 grams (0.142 mole) of 4- chlorobenzaldehyde and 52.0 grams (0.171 mole) of formylmethylenetriphenylphosphorane in 215 mL of

acetonitrile was heated at 60ºC for about 18 hours. The reaction mixture was cooled, and 50 grams of silica gel was added. The acetonitrile was removed under reduced pressure. The silica gel-reaction mixture was placed on the top of a silica gel column and was eluted with 1:2 - ethyl acetate and hexane. The appropriate fractions were combined and concentrated under reduced pressure to a residual solid. The solid was recrystallized with 1:6 - ethyl acetate and hexane, yielding 11.8 grams of 4- chlorocinnamaldehyde; m.p. 51-56ºC. The nmr spectrum was consistent with the proposed structure.

Step B Synthesis of 2-ethoxycarbonyl-3-(4- chlorophenyl)cyclohex-5-enone as an

intermediate

This compound was prepared in a manner analogous to that of Example 5, Step A, using 11.3 grams (0.071 mole) of 4-chlorocinnamaldehyde, 9.0 grams (0.069 mole) of ethyl acetoacetate, and 0.3 gram (0.002 mole) of the sodium salt of ethyl acetoacetate in 26 mL of ethanol. The crude reaction mixture was concentrated under reduced pressure to a residue. The residue was

dissolved in diethyl ether, washed with water, and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 20.6 grams of material that was about 50% pure 2-ethoxycarbonyl-3-(4-chlorophenyl)cyclohex-5- enone.

Step C Synthesis of ethyl 6-(4-chlorophenyl) salicylate as an intermediate To a stirred solution of 20.0 grams (0.036 mole) of about 50% pure 2-ethoxycarbonyl-3-(4-chlorophenyl)- cyclohex-5-enone in 100 mL of toluene was added 8.1 grams (0.36 mole) of 2,3-dichloro-5,6-dicyano-1,4- benzoquinone. Upon completion of addition, the reaction mixture was warmed to 80-85ºC where it was stirred for about 18 hours. After this time the reaction mixture was cooled, and 200 mL of diethyl ether was added. The solution was washed with three 200 mL portions of water and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:4 - ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure to a residue. An nmr spectrum of the residue indicated it to be about 80% pure reaction product. The residue was subjected to a second column chromatography on silica gel. Elution was accomplished using 7.5:92.5 ethyl acetate in hexane.

The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.8 gram of ethyl 6-(4- chlorophenyl) salicylate; m.p. 51-54ºC.

Step D Synthesis of 6-(4-chlorophenyl) salicylic acid as an intermediate

This compound was prepared in a manner analogous to that of Example 5, Step C, using 0.80 gram (0.003 mole) of ethyl 6-(4-chlorophenyl) salicylate, and 0.57 gram (0.009 mole) of 85% potassium hydroxide in 6.6 mL of ethanol and 12.1 mL of water. The yield of 6-(4- chlorophenyl) salicylic acid was 0.73 gram. Step E Synthesis of phenylmethyl 6-(4- chlorophenyl) salicylate as an intermediate

Under a nitrogen atmosphere, a solution of 0.68 gram (0.003 mole) of 6-(4-chlorophenyl) salicylic acid in 17 mL of dimethylformamide was stirred, and 0.11 gram

(0.003 mole) of 60% sodium hydride (in mineral oil) was added. Upon completion of addition, the reaction mixture was stirred for 30 minutes, then 0.35 gram

(0.003 mole) of phenylmethyl chloride was added,

followed by 0.41 gram (0.003 mole) of sodium iodide.

Upon completion of addition the reaction mixture was stirred for about four days. After this time the reaction mixture was poured into aqueous 1N hydrochloric acid. The mixture was extracted with diethyl ether.

The extract was washed with water and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 5:95 - ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.56 gram of

phenylmethyl 6-(4-chlorophenyl) salicylate. The nmr spectrum was consistent with the proposed structure.

Step F Synthesis of 2-chloro-4,6-dimethoxy-1,3,5- triazine as an intermediate

To a stirred mixture of 45.0 grams of methanol and 5.0 grams of water were added 16.8 grams (0.20 mole) of sodium bicarbonate and 18.5 grams (0.1 mole) of cyanuric chloride. The addition caused the reaction mixture temperature to rise to 35ºC and the liberation of carbon dioxide gas. After the gas evolution slowed, the reaction mixture was heated to reflux where it was stirred for 30 minutes. The. reaction mixture was cooled, diluted with water, and the resultant solid was collected by filtration. The solid was washed

repeatedly with water and was dried, yielding 13.0 grams of 2-chloro-4,6-dimethoxy-1,3,5-triazine, m.p. 74-76°C. Recrystallization of the solid from heptane raised the melting point to 75-76ºC.

Step G Synthesis of phenylmethyl 2-(4,6-dimethoxy- 1,3,5-triazin-2-yloxy)-6-(4- chlorophenyl)benzoate as an intermediate This compound was prepared in a manner analogous to that of Example 7, Step E, using 0.55 gram (0.002 mole) of phenylmethyl 6-(4-chlorophenyl) salicylate, 0.28 gram (0.002 mole) of 2-chloro-4,6-dimethoxy-1,3,5-triazine, and 0.06 gram (0.002 mole) of 60% sodium hydride (in mineral oil) in 5.1 mL of dimethylformamide. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous 1N hydrochloric acid, with water, and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 1:1.5-ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.63 gram of

phenylmethyl 2-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)-6- (4-chlorophenyl)benzoate. The nmr spectrum was

consistent with the proposed structure. Step H Synthesis of 2-(4,6-dimethoxy-1,3,5-triazin-2- yloxy)-6-(4-chlorophenyl)benzoic acid (Compound 113) A solution of 0.63 gram (0.001 mole) of phenylmethyl 2-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)-6-(4- chlorophenyl)benzoate in 14 mL of acetic acid and 48 mL of ethanol was placed in a 250 mL Parr hydrogenation bottle along with 0.02 gram of 10% palladium on

charcoal. The mixture was hydrogenated using a Parr hydrogenation apparatus. Upon the completion of the uptake of the theoretical amount of hydrogen gas, the reaction mixture was filtered through diatomaceous earth. The filtrate was washed with methylene chloride, and the ethanol/acetic acid layer was concentrated under reduced pressure to remove the ethanol. The concentrate was shaken with water and ethyl acetate. The organic layer was washed with an aqueous solution saturated with sodium chloride and then was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 0.43 gram of 2-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)-6-(4- chlorophenyl) benzoic acid. The nmr spectrum was consistent with the proposed structure.

EXAMPLE 9

Synthesis of isopropylideneamino 2-(4,6-dimethoxy- pyrimidin-2-yloxy)-6-phenylbenzoate

(Compound 90)

Step A Synthesis of 4-nitrophenyl 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-phenylbenzoate as an intermediate Under a nitrogen atmosphere a stirred solution of 1.0 gram (0.003 mole) of 2-(4,6-dimethoxypyrimidin-2- yloxy)-6-phenylbenzoic (prepared as described in Example 1) in 30 mL of methylene chloride was cooled to 0°C, and 0.3 gram (0.003 mole) of 4-nitrophenol was added. When the phenol had dissolved, 0.6 gram (0.003 mole) of dicyclohexylcarbodiimide (DCC) was added. Upon

completion of addition, the reaction mixture was stirred at 0ºC for one hour, and then was allowed to warm to ambient temperature where it was stirred for an

additional one hour. The reaction mixture was filtered, and the filtrate was washed with fresh methylene

chloride. The combined filtrate and wash was

concentrated under reduced pressure to a residue. The residue was dissolved in diethyl ether and filtered.

The filtrate was concentrated under reduced pressure, yielding 1.4 grams of 4-nitrophenyl 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-phenylbenzoate. The nmr spectrum was consistent with the proposed structure. Step B Synthesis of isopropylideneamino 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-phenylbenzoate (Compound 90)

Under a nitrogen atmosphere a stirred solution of 1.4 grams (0.003 mole) of 4-nitrophenyl 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-phenylbenzoate, 0.3 gram (0.004 mole) of acetone oxime, and 0.8 gram (0.006 mole) of potassium carbonate in 55 mL of acetonitrile was heated at reflux for about 1.5 hours. After this time the reaction mixture was cooled to ambient temperature and was filtered through a short column of silica gel. The filter cake was washed with ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 ethyl acetate and heptane. The appropriate fractions were combined and concentrated under reduced pressure to a residue. The residue was dissolved in ethyl acetate and then was washed with aqueous 5% potassium hydroxide. The organic layer was dried with magnesium sulfate and filtered.

The filtrate was concentrated under reduced pressure, yielding 0.3 gram of isopropylidineamino 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-phenylbenzoate. The nmr spectrum was consistent with the proposed structure.

EXAMPLE 10

Synthesis of propyn-2-yl 2-(4,6-dimethoxy- pyrimidin-2-yloxy)-6-phenylbenzoate

(Compound 78)

Under a nitrogen atmosphere a solution of 0.38 gram (0.001 mole) of 2-(4,6-dimethoxypyrimidin-2-yloxy)-6- phenylbenzoic acid (Compound 1 - prepared in the manner of Example 5) and 0.22 gram (0.002 mole) of potassium bicarbonate in 15 mL of dimethylformamide was warmed to 85°C where it was stirred for one hour. After this time a catalytic amount of potassium iodide and 0.19 gram (0.002 mole) of a solution of 80% propyn-2-yl bromide in toluene were added. Upon completion of addition, the reaction mixture was stirred at 85ºC for an additional one hour. After this time the reaction mixture was cooled and with vigorous stirring, was poured into aqueous dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered through a short column of silica gel. The column was washed with ethyl acetate. The wash and the extract were combined and concentrated under reduced pressure, yielding 0.32 gram of propyn-2-yl 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-phenylbenzoate. The nmr spectrum was consistent with the proposed structure. EXAMPLE 11

Synthesis of the ammonium salt of 2-(4,6-dimethoxy- pyrimidin-2-yloxy)-6-phenylbenzoic acid

(Compound 106) A solution of 0.57 gram (0.002 mole) of 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-phenylbenzoic acid, about 0.2 gram of ammonium hydroxide, 5 mL of ethanol and 5 mL of tetrahydrofuran was stirred in a sealed vessel for about 18 hours. A solid was collected by filtration and was washed with a small portion of acetone, yielding 0.18 gram of the ammonium salt of 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-phenylbenzoic acid; m.p. 149-151°C. The nmr spectrum was consistent with the proposed structure. A few drops of. ammonium hydroxide were added to the filtrate and the mixture was

concentrated under reduced pressure to a residual solid. The solid was recrystallized from acetone/heptane yielding 0.10 gram of the ammonium salt of 2-(4,6- dimethoxypyrimidin-2-yloxy)-6-phenylbenzoic acid; m.p. 147-151ºC. The nmr spectrum was consistent with the proposed structure. Both fractions were combined.

EXAMPLE 12

Synthesis of 2-(5-chloro-4,6-dimethoxypyrimidin- 2-yloxy)-6-phenylbenzoic acid

(Compound 62)

Step A Synthesis of 5-chloro-4,6-dimethoxy-2- methylsulfonylpyrimidine as an intermediate Under a nitrogen atmosphere a stirred solution of 9.7 grams (0.045 mole) of 4,6-dimethoxy-2- methylsulfonylpyrimidine and 6.0 grams (0.045 mole) of N-chlorosuccinimide in 25 mL of glacial acetic acid was heated at 95-100ºC for three hours. After this time the reaction mixture was allowed to cool to ambient

temperature where it was stirred for about 18 hours.

Thin layer chromatographic analysis of the reaction mixture indicated that the reaction had not gone to completion. The reaction mixture was then heated at

80ºC for 1.5 hours, at 90-95ºC for one hour, and then at 115ºC for 1.3 hours. After this time the reaction mixture was poured into ice-water. The resultant solid was collected by filtration and was washed with water. The dried solid was subjected to column chromatography on silica gel. Elution was accomplished using 3:1 ethyl acetate and heptane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 3.8 grams of 5-chloro-4,6-dimethoxy-2- methylsulfonylpyrimidine; m.p. 184-185ºC. The nmr spectrum was consistent with the proposed structure.

Step B Synthesis of 2-(5-chloro-4,6- dimethoxypyrimidin-2-yloxy)-6- phenylbenzoic acid

(Compound 62)

This compound was prepared in a manner analogous to that of Example 5, Step D, using 0.50 gram (0.002 mole) of 6-phenylsalicylic acid (prepared as in Example 4, Steps A-C), 0.89 gram (0.004 mole) of 5-chloro-4,6- dimethoxy-2-methylsulfonylpyrimidine, and 0.18 gram (0.006 mole) of 80% sodium hydride in 60 mL of

tetrahydrofuran. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in about 70 mL of water and the solution was washed with three 50 mL portions of ethyl acetate. The aqueous layer was acidified with 20 mL of aqueous 1N hydrochloric acid. The mixture was then extracted with three 50 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The solid was washed with pentane, yielding 0.84 gram of 2-(5-chloro-4,6-dimethoxypyrimidin-2-yloxy)-6- phenylbenzoic acid. The nmr spectrum was consistent with the proposed structure.

HERBICIDAL ACTIVITY

The plant test species used in demonstrating the herbicidal activity of compounds of this invention include velvetleaf (AbutiIon theoprasti), blackgrass (Alopecurus mγosuroides), soybean (Glvcine max),

morningglory (Ipomea lacunosa or Ipomea hederacea), green foxtail (Setaria viridis), johnsongrass (Sorghum halepense), common chickweed (Stellaria media), wheat Triticum aestivium), common cocklebur (Xanjthium

pensylvanicum), and corn (Zea mays). Preparation of Flats

Preemergence:

Two disposable fiber flats (8 cm x 15 cm x 25 cm) for each rate of application for each candidate herbicide for preemergence testing are filled to an approximate depth of 6.5 cm with steam sterilized sandy loam soil. The soil is leveled and impressed with a template to provide six evenly spaced furrows 13 cm long and 0.5 cm deep in each flat. Seeds of corn, wheat, soybean, johnsongrass, and green foxtail are planted in five of the furrows of the first flat (the sixth furrow is left unplanted), and seeds of morningglory, velvetleaf, common cocklebur, blackgrass and common chickweed are planted in the five furrows of the second flat. The template is again employed to firmly press the seeds into place. A topping soil of equal portions of sand and sandy loam soil is placed uniformly on top of each flat to a depth of approximately 0.5 cm.

The flats for the preemergence test were first watered and then drenched with a solution of test compound as described below. The flats were placed in a greenhouse and watered regularly at the soil surface for 21 days at which time phytotoxicity data were recorded. Postemergence:

Two flats for each rate of application for each herbicide candidate are also prepared for postemergence application. The postemergence flats are prepared in the manner as described above for preemergence flats.

The flats for the postemergence test were placed in a greenhouse and watered for 8-10 days after which the foliage of the emerged test plants was sprayed with a solution of the test compound. After spraying, the foliage was kept dry for 24 hours and then watered regularly for 21 days after which phytotoxicity data were recorded.

Application of Herbicides

In both the preemergence and postemergence tests, the candidate herbicides were applied as aqueous acetone solutions at rates equivalent to 8.0 kilograms/hectare (kg/ha) and submultiples thereof, i.e., 4.0 kg/ha, 2.0 kg/ha, and so on. Preemergence applications were made as soil drenches using 100 mL of test solution of appropriate concentration for each of the two

flats/compounds. Postemergence applications were made as foliar sprays using 5 mL of test solution for each of the two flats. Preparation of Test Solutions

For flats of the size described above, an application rate of 8.0 kg/ha of test compound is equivalent to 0.025 gram/flat. A stock solution of 0.2 gram of test compound in 40 mL of acetone containing 0.5% v/v of sorbitan monolaurate emulsifier/solubilizer was

prepared. For the 8.0 kg/ha preemergence test, 10 mL of the stock solution was diluted with water to give 200 mL of test solution for application as a soil drench to both flats, 100 mL/flat. For the 8.0 kg/ha

postemergence test, 10 mL of the stock solution was used undiluted as a spray, 5 mL/flat.. The remaining 20 mL of stock solution was diluted with an equal volume of acetone-emulsifier to give 40 mL of a second stock solution, containing 0.1 gram of test compound, and the process above repeated, i.e., 20 mL of the solution being used for the 4.0 kg/ha application rate, and 20 mL for the preparation of lower rate test solutions by the same process.

Phytotoxicity data are taken as percent control.

Percent control is determined by a method similar to the 0 to 100 rating system disclosed in "Research Methods in Weed Science," 2nd ed., B. Truelove, Ed.; Southern Weed Science Society; Auburn University, Auburn, Alabama, 1977. The rating system is as follows:

Herbicide Rating System

Rating Description

Percent of Main Crop Weed

Control Categories Description Description

0 No effect No crop No weed

reduction control or injury

10 Slight disVery poor weed coloration control or stunting

20 Slight Some disPoor weed

effect coloration, control

stunting or

stand loss

30 Crop injury Poor to defimore pronounced cient weed but not lasting control

40 Moderate injury, Deficient weed crop usually control recovers

50 Moderate Crop injury Deficient to effect more lasting, moderate weed recovery doubtcontrol ful

60 Lasting crop Moderate weed injury, no control recovery

70 Heavy injury and Control somestand loss what less than satisfactory

80 Severe Crop nearly desSatisfactory troyed, a few to good weed survivors control

90 Only occasional Very good to live plants left excellent

control

100 Complete Complete crop Complete weed effect destruction destruction For herbicidal application, the active compounds are formulated into herbicidal compositions by admixture in herbicidally effective amounts with adjuvants and carriers normally employed in the art for facilitating the dispersion of active ingredients for the particular utility desired, recognizing the fact that the formulation and mode of application of a toxicant may affect the activity of the material in a given application. Thus, for agricultural use the present herbicidal compounds may be formulated as granules of relatively large particle size, as water-soluble or water-dispersible granules, as powdery dusts, as wettable powders, as emulsifiable concentrates, as solutions, or as any of several other known types of formulations, depending on the desired mode of application.

These herbicidal compositions may be applied either as water-diluted sprays, or dusts, or granules to the areas in which suppression of vegetation is desired.

These formulations may contain as little as 0.1%, 0.2% or 0.5% to as much as 95% or more by weight of active ingredient.

Dusts are free flowing admixtures of the active ingredient with finely divided solids such as talc, natural clays, kieselguhr, flours such as walnut shell and cottonseed flours, and other organic and inorganic solids which act as dispersants and carriers for the toxicant; these finely divided solids have an average particle size of less than about 50 microns. A typical dust formulation useful herein is one containing 1.0 part or less of the herbicidal compound and 99.0 parts of talc.

Wettable powders, also useful formulations for both pre- and postemergence herbicides, are in the form of finely divided particles which disperse readily in water or other dispersant. The wettable powder is ultimately applied to the soil either as a dry dust or as an emulsion in water or other liquid. Typical carriers for wettable powders include Fuller's earth, kaolin clays, silicas, and other highly absorbent, readily wet inorganic diluents. Wettable powders normally are prepared to contain about 5-80% of active ingredient, depending on the absorbency of the carrier, and usually also contain a small amount of a wetting, dispersing or emulsifying agent to facilitate dispersion. For example, a useful wettable powder formulation contains 80.8 parts of the herbicidal compound, 17.9 parts of

Palmetto clay, 1.0 part of sodium lignosulfonate and 0.3 part of sulfonated aliphatic polyester as wetting agents. Other wettable powder formulations are: Component: % by Wt.

Active ingredient 40. 00

Sodium lignosulfonate 20. 00

Attapulgite clay 40. 00 Total 100. 00

Component: % by Wt.

Active ingredient 90. 00

Dioctyl sodium sulfosuccinate 0. 10

Synthetic fine silica 9.90 Total 100.00

Component: % by Wt. Active ingredient 20.00 Sodium alkylnaphthalenesulfonate 4.00 Sodium lignosulfonate 4.00

Low viscosity methyl cellulose 3.00 Attapulgite clay 69.00 Total 100.00 Component: % by Wt. Active ingredient 25.00 Base: 75.00 96% hydrated aluminum magnesium silicate

2% powdered sodium lignosulfonate

2% powdered anionic sodium alkylnaphthalenesulfonate

Total 100.00

Frequently, additional wetting agent and/or oil will be added to the tank-mix for postemergence application to facilitate dispersion on the foliage and absorption by the plant.

Other useful formulations for herbicidal applications are emulsifiable concentrates (ECs) which are homogeneous liquid or paste compositions dispersible in water or other dispersant, and may consist entirely of the herbicidal compound and a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone, or other non-volatile organic solvent. For herbicidal

application these concentrates are dispersed in water or other liquid carrier, and normally applied as a spray to the area to be treated. The percentage by weight of the essential active ingredient may vary according to the manner in which the composition is to be applied, but in general comprises 0.5 to 95% of active ingredient by weight of the herbicidal composition.

The following are specific examples of emulsifiable concentrate formulations:

Component: % by Wt.

Active ingredient 53.01

Blend of alkylnaphthalenesulfonate

and polyoxyethylene ethers 6.00

Epoxidized soybean oil 1.00 Xylene 39.99

Total 100.00 Component: % by Wt.

Active ingredient 10.00

Blend of alkylnaphthalenesulfonate

and polyoxyethylene ethers 4.00 Xylene 86.00

Total 100.00

Flowable formulations are similar to ECs except that the active ingredient is suspended in a liquid carrier, generally water. Flowables, like ECs, may include a small amount of a surfactant, and contain active ingredient in the range of 0.5 to 95%, frequently from 10 to 50%, by weight of the composition. For application, flowables may be diluted in water or other liquid vehicle, and are normally applied as a spray to the area to be treated.

The following are specific examples of flowable formulations:

Component: % by Wt. Active ingredient 46.00 Colloidal magnesium aluminum silicate 0.40 Sodium alkylnaphthalenesulfonate 2.00 Paraformaldehyde 0.10 Water 40.70

Propylene glycol 1.50 Acetylenic alcohols 2.50 Xanthan gum 0.80 Total 100.00

Component: % by Wt. Active ingredient 45.00

Water 48.50

Purified smectite clay 2.00

Xanthan gum 0.50

Sodium alkylnaphthalenesulfonate 1.00 Acetylenic alcohols 3.00 Total 100.00 Typical wetting, dispersing or emulsifying agents used in agricultural formulations include, but are not limited to, the alkyl and alkylaryl sulfonates and sulfates and their sodium salts; alkylaryl polyether alcohols; sulfated higher alcohols; polyethylene oxides; sulfonated animal and vegetable oils; sulfonated petroleum oils; fatty acid esters of polyhydric alcohols and the ethylene oxide addition products of such esters; and the addition product of long-chain mercaptans and ethylene oxide. Many other types of useful surfaceactive agents are available in commerce. The surfaceactive agent, when used, normally comprises from 1 to 15% by weight of the composition.

Other useful formulations include simple solutions or suspensions of the active ingredient in a relatively non-volatile solvent such as water, corn oil, kerosene, propylene glycol, or other suitable solvents. The following illustrate specific suspensions: Oil Suspension: % b y Wt .

Active ingredient 25 . 00

Polyoxyethylene sorbitol hexaoleate 5 . 00

Highly aliphatic hydrocarbon oil 70 . 00 Total 100 . 00

Aqueous Suspension: % by Wt.

Active ingredient 40 . 00

Polyacrylic acid thickener 0 . 30

Dodecylphenol polyethylene glycol ether 0 .50 Disodium phosphate 1. 00

Monosodium phosphate 0. 50

Polyvinyl alcohol 1. 00

Water 56 . 70

Total 100. 00 Other useful formulations for herbicidal applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene, or other organic solvents. Granular formulations, wherein the toxicant is carried on relatively coarse particles, are of particular utility for aerial distribution or for penetration of cover crop canopy. Pressurized sprays, typically aerosols wherein the active ingredient is dispersed in finely divided form as a result of vaporization of a low boiling dispersant solvent carrier, such as the Freon fluorinated hydrocarbons, may also be used. Water-soluble or water- dispersible granules are also useful formulations for herbicidal application of the present compounds. Such granular formulations are free-flowing, non-dusty, and readily water-soluble or water-miscible. The soluble or dispersible granular formulations described in U.S.

patent No. 3,920,442 are useful herein with the present herbicidal compounds. In use by the farmer on the field, the granular formulations, emulsifiable

concentrates, flowable concentrates, solutions, etc., may be diluted with water to give a concentration of active ingredient in the range of say 0.1% or 0.2% to 1.5% or 2%.

The active herbicidal compounds of this invention may be formulated and/or applied with insecticides, fungicides, nematicides, plant growth regulators, fertilizers, or other agricultural chemicals and may be used as effective soil sterilants as well as selective herbicides in agriculture. In applying an active compound of this invention, whether formulated alone or with other agricultural chemicals, an effective amount and concentration of the active compound is of course employed; the amount may be as low as, for example, about 1 to 250 g/ha, preferably about 4 to 30 g/ha. For field use, where there are losses of herbicide, higher application rates (for example, four times the rates mentioned above) may be employed.

The active herbicidal compounds of this invention may be used in combination with other herbicides, for example, they may be mixed with, say, an equal or larger amount of a known herbicide such as chloroacetanilide herbicides such as 2-chloro-N-(2,6-diethylphenyl)-N- (methoxymethyl)acetamide (alachlor), 2-chloro-N-(2- ethyl-6-methylphenyl-N-(2-methoxy-1- methylethyl)acetamide (metolachlor), and N-chloroacetyl- N-(2,6-diethylphenyl) glycine (diethatyl-ethyl);

benzothiadiazinone herbicides such as 3-(1-methylethyl)- (1H)-2,1,3-benzothiadiazin-4-(3H)-one-2,2-dioxide

(bentazon); triazine herbicides such as 6-chloro-N- ethyl-N-(1-methylethyl)-1,3,5-triazine-2,4-diamine

(atrazine), and 2-[4-chloro-6-(ethylamino)-1,3,5- triazin-2-yl]amino-2-methylpropanenitrile (cyanazine); dinitroaniline herbicides such as 2, 6-dinitro-N,N- dipropyl-4-(trifluoromethyl) benzeneamine (trifluralin); aryl urea herbicides such as N'-(3,4-dichlorophenyl)- N,N-dimethylurea (diuron) and N,N-dimethyl-N'-[3- (trifluoromethyl) phenyl]urea (fluometuron); and 2-[(2- chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone.

It is apparent that various modifications may be made in the formulation and application of the compounds of this invention without departing from the inventive concepts herein as defined in the claims.

*Rate of application is in grams/hectare

*Rate of application is in grams/hectare

Claims

Claims:

1. A compound characterized by the formula

in which

A is 0, S, or -N-R² in which R² is hydrogen, alkyl, -C(O)-NH₂ or -C(O) alkyl;

B is -CH-, -CR⁴- or -N-;

R and R¹ are independently alkyl, alkoxy,

haloalkoxy, halogen or alkylamino; and

R⁴ is hydrogen, alkyl, phenyl, nitro, cyano, amino, alkoxycarbonyl, or halogen;

M is hydrogen, alkyl, alkenyl, alkynyl, phenylalkyl, haloalkyl, cyanoalkyl, alkylthioalkyl, dialkylamino- alkyl, alkylsulfonylalkyl, alkoxycarbonylalkyl, carboxyalkyl, di(alkoxycarbonyl)alkyl, dialkylaminocarbonyl- alkyl, dialkylideneamino, alkylthioalkylideneamino, optionally alkyl substituted ammonium, optionally hydroxyalkyl substituted ammonium, the cation of an alkali or alkaline earth metal, or phenyl optionally substituted with nitro, halo, alkyl, haloalkyl or alkyloxy; and

Q is

in which X, Y, and P are independently hydrogen,

halogen, lower alkyl, lower alkoxy, lower haloalkyl, lower alkylthio, lower alkylsulfonyl,

alkylsulfonylamino, alkylsulfonyloxy, arylsulfonyloxy, di(aryl sulfonyl)amino, benzylamino, alkylcarbonylamino, aminocarbonylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylsulfonylamino, phenylsulfonylamino, acid salts of the noted amino compounds, lower alkenyl, lower alkynyl, lower alkenyloxy, lower alkynyloxy, cyano, nitro or amino, or X and Y taken together form a C₁ to C₃

alkylenedioxy heterocyclic ring; or an aromatic

heterocycle selected from thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine.

2. A compound as in claim 1 characterized in that M is H, A is O, B is -CH- and each of R and R¹ is methoxy .

3. A compound as in claim 2 characterized in that Q is

in which X, Y, and P are independently hydrogen, halogen, alkyl, alkoxy, haloalkyl, alkylthio,

alkylsulfonyl, alkenyl, alkynyl, alkenyloxy, alkynyloxy, nitro or amino, or X and Y taken together form a C₁ to

C₃ alkylenedioxy heterocyclic ring.

4. A compound as in claim 2 characterized in that Q is thiophene.

5. A compound as in claim 3 characterized in that P and Y are hydrogen.

6. A compound as in claim 5 characterized in that X is halogen or lower alkyl, or lower alkoxy.

7. A compound as in claim 6 characterized in that X is chlorine or fluorine.

8. A compound as in claim 6 characterized in that X is methyl.

9. A compound as in claim 6 characterized in that X is positioned at C₄ or C₃ of the phenyl ring.

10. An herbicidal composition containing an herbicidally effective amount of a compound of claim 1 in admixture with a suitable carrier.

11. A process for preparing a compound of the formula

in which

A is O, S, or -N-R² in which R² is hydrogen, alkyl, -C(O)-NH₂ or -C(O)alkyl;

B is -CH-, -CR⁴- or -N-;

R and R¹ are independently alkyl, alkoxy,

haloalkoxy, halogen or alkylamino; and

R⁴ is hydrogen, alkyl, phenyl, nitro, cyano, amino, alkoxycarbonyl, or halogen; and

Q is

in which X, Y, and P are independently hydrogen, halogen, lower alkyl, lower alkoxy, lower haloalkyl, lower alkylthio, lower alkylsulfonyl,

alkylsulfonylamino, alkylsulfonyloxy, arylsulfonyloxy, di(aryl sulfonyl) amino, benzylamino, alkylcarbonylamino, aminocarbonylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylsulfonylamino, phenylsulfonylammo, acid salts of the noted amino compounds, lower alkenyl, lower alkynyl, lower alkenyloxy, lower alkynyloxy, nitro or amino, or X and Y taken together form a C₁ to C₃ alkylenedioxy heterocyclic ring; or an aromatic heterocycle selected from thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine characterized in that a compound of the formula

a. wherein T is formyl, the compound is oxidized, or

b. wherein T is cyano, alkyloxycarbonyl or aryloxycarbonyl, the compound is hydrolyzed, or

c. wherein T is di(alkoxy)methyl, the compound is hydrolyzed, followed by oxidation, or

d. wherein T is methylcarbonyl, the compound is oxidized using a hypohalite, or

e. wherein T is halogen, the compound is reacted with an alkyl lithium compound followed by treatment with carbon dioxide and acid.

12. A process for preparing a compound of the formula

in which

A is O , S , or -N-R² in which R² is hydrogen, alkyl , -C (O) -NH₂ or -C (O) alkyl ;

B is -CH- , -CR⁴- or -N- ;

R and R¹ are independently alkyl, alkoxy,

haloalkoxy, halogen or alkylamino;

T is formyl, cyano, methyl carbonyl, dialkoxymethyl, -C(OH)OH (alkyl or aryl) oxycarbonyl , or halogen ; and

R⁴ is hydrogen, alkyl , phenyl, nitro, cyano, amino, alkoxycarbonyl, or halogen;

M is hydrogen, alkyl, alkenyl, alkynyl, phenylalkyl, haloalkyl, cyanoalkyl, alkylthioalkyl, dialkylamino- alkyl, alkylsulfonylalkyl, alkoxycarbonylalkyl, carboxyalkyl, di(alkoxycarbonyl)alkyl, dialkylaminocarbonyl- alkyl, dialkylideneamino, alkylthioalkylideneamino, optionally alkyl substituted ammonium, optionally hydroxyalkyl substituted ammonium, the cation of an alkali or alkaline earth metal, or phenyl optionally substituted with nitro, halo, alkyl, haloalkyl or alkyloxy; and

Q is

in which X, Y, and P are independently hydrogen,

halogen, lower alkyl, lower alkoxy, lower haloalkyl, lower alkylthio, lower alkylsulfonyl,

alkylsulfonylamino, alkylsulfonyloxy, arylsulfonyloxy, di(aryl sulfonyl) amino, benzylamino, alkylcarbonylamino, aminocarbonylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylsulfonylamino, phenylsulfonylamino, acid salts of the noted amino compounds, lower alkenyl, lower alkynyl, lower alkenyloxy, lower alkynyloxy, nitro or amino, or X and Y taken together form a C₁ to C₃ alkylenedioxy heterocyclic ring; or an aromatic heterocycle selected from thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine which process is characterized by the reaction of a compound of the formula

with a base and a compound of the formula

in which G is methylsulfonyl or chloro.

13. A process for preparing a compound of the formula

in which

A is O, S , or -N-R² in which R² is hydrogen, alkyl , -C (O) -NH₂ or -C (O) alkyl ;

B is -CH-, -CR⁴- or -N- ;

R and R¹ are independently alkyl, alkoxy,

haloalkoxy, halogen or alkylamino; and

R⁴ is hydrogen, alkyl, phenyl, nitro, cyano, amino, alkoxycarbonyl, or halogen;

M is hydrogen, alkyl, alkenyl, alkynyl, phenylalkyl, haloalkyl, cyanoalkyl, alkylthioalkyl, dialkylamino- alkyl, alkylsulfonylalkyl, alkoxycarbonylalkyl, carboxyalkyl, di(alkoxycarbonyl) alkyl, dialkylaminocarbonyl- alkyl, dialkylideneamino, alkylthioalkylideneamino, optionally alkyl substituted ammonium, optionally hydroxyalkyl substituted ammonium, the cation of an alkali or alkaline earth metal, or phenyl optionally substituted with nitro, halo, alkyl, haloalkyl or alkyloxy; and

Q is

in which X, Y, and P are independently hydrogen,

halogen, lower alkyl, lower alkoxy, lower haloalkyl, lower alkylthio, lower alkylsulfonyl,

alkylsulfonylamino, alkylsulfonyloxy, arylsulfonyloxy, di(aryl sulfonyl) amino, benzylamino, alkylcarbonylamino, aminocarbonylamino, alkoxycarbonyl, alkylcarbonyloxy, alkylsulfonylamino, phenylsulfonylamino, acid salts of the noted amino compounds, lower alkenyl, lower alkynyl, lower alkenyloxy, lower alkynyloxy, nitro or amino, or X and Y taken together form a C₁ to C₃ alkylenedioxy heterocyclic ring; or an aromatic heterocycle selected from thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine characterized in that a compound of the formula

a. wherein T is carboxyl, the compound is

esterified or

b. wherein T is -C(O)Cl is reacted with an alcohol or phenol.

14. A method for controlling unwanted plant growth which comprises applying to the locus where control is desired an herbicidally effective amount of the

composition of claim 1.