Cycloimido-substituted benzofused heterocyclic herbicides

BACKGROUND OF THE INVENTION
The present invention relates generally to novel herbicidal compounds and methods for their use in controlling unwanted plant species in agriculture. In particular, the present invention pertains to cycloimido-substituted benzofused heterocyclic herbicides, and more particularly it pertains to herbicides in which the benzofused heterocycle is a benzofuran, benzimidazole, a 2,3-dihydrobenzimidazole, or indole having a cycloimido moiety which is a 1-substituted-6-trifluoromethyl-2,4-pyrimidinedione-3-yl, a 1-substituted-6-trifluoromethyl-1,3,5-triazine-2,4-dion-1-yl, a 3,4,5,6-tetrahydrophthalimid-1-yl, a 4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl, a 5,6,7,8-tetrahydro-1H,3H-[1,3,4]thiadiazolo[3,5-a]pyridazineimin-1-yl, or a 1,6,8-triazabicyclo[4.3.0]-nonane-7,9-dion-8-yl ring.
SUMMARY OF THE INVENTION
It has now been found that certain cycloimido-substituted benzofused heterocyclic compounds are useful as pre-emergent and postemergent herbicides. These novel compounds are represented by formula I: ##STR2## where J is a 1-substituted-6-trifluoromethyl-2,4-pyrimidinedione-3-yl, a 1-substituted-6-trifluoromethyl-1,3,5-triazine-2,4-dion-1-yl, a 3,4,5,6-tetrahydrophthalimid-1-yl, a 4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl, a 5,6,7,8-tetrahydro-1H,3H-[1,3,4]thiadiazolo[3,5-a]pyridazineimin-1-yl, or a 1,6,8-triazabicyclo[4.3.0]-nonane-7,9-dion-8-yl ring attached at the 7 position of a benzofuran, benzoxazole, 2,3-dihydrobenzimidazole, indole or benzimidazole, and X is selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, and amino. Preferred R groups are optionally substituted alkyl groups.
DETAILED DESCRIPTION OF THE INVENTION
Certain cycloimido-substituted benzofused heterocyclic compounds have now been found to be useful as pre- and postemergent herbicides. These compounds are represented by formula I: ##STR3## where (1) A is nitrogen double-bonded to position 2 and B is oxygen;
(2) A is oxygen and B is CR.sup.1 double bonded to position 2;
(3) A is NH and B is nitrogen double-bonded to position 2;
(4) A is nitrogen double bonded to position 2 and B is NR.sup.2 ;
(5) A is CH double bonded to position 2 and B is NR.sup.2 ;
(6) A is NH and B is CR.sup.1 double bonded to position 2; or
(7) A and B are NH
R is hydrogen, hydroxy, mercapto, straight or branched chain lower alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, alkenyl, haloalkyl, hydroxyalkyl, haloaryl, alkoxyaryl, arylalkyl, aryloxyalkyl, haloarylalkyl, alkylthio, heterocyclyl, alkoxyalkyl, alkoxylalkyloxyalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, aminocarbonyloxyalkyl, aminoalkyl, cyanoalkyl, aminoalkenyl, carboxy, carboxyalkyl, alkylcarboxy, alkylcarboxyalkyl, formyl, aminocarbonyl, amino, oxygen, cyano, nitro, alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, alkoxycarbonyloxyalkyl, alkylcarboxylalkoxy, alkoxycarbonylamino, alkoxycarbonylalkylaminoalkyl, aryliminoalkyl, (aryl)(alkoxy)alkyl, (aryl)(alkylcarbonyloxy)alkyl, arylalkoxyalkyl, cyanoalkylthio, alkynylalkylthio, arylalkylthio, cyanothio, cyanothioalkyl, alkoxycarbonylalkylthio, aminocarbonylalkylthio, alkenylalkylthio, haloalkylalkynylalkylthio, aminocarbonyloxyalkyl, arylalkylcarbonylaminoalkyl, (hydroxy)(aryl)alkyl, alkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, alkoxycarbonyl, and alkenyloxy, where the amino group may be substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, aryl, alkylsufonyl, or haloalkylsulfonyl;
R.sup.1 is hydrogen, lower alkyl, or haloalkyl;
R.sup.2 is hydrogen, alkyl, haloalkyl, CO.sub.2 (alkyl), CH.sub.2 CO.sub.2 (alkyl), CH.sub.2 CONH--alkyl, CH.sub.2 CON(alkyl).sub.2, CH.sub.2 CO.sub.2 H, CH.sub.2 OCH.sub.3, SO.sub.2 (alkyl), CH.sub.2 CH.dbd.CH.sub.2, CH.sub.2 C.tbd.CH.
X is selected from hydrogen, F, Cl, Br, alkyl, haloalkyl, CN, NO.sub.2, and NH.sub.2 ;
n is 0-3;
J is selected from ##STR4## and R.sup.3 is selected from hydrogen, alkyl, haloalkyl, CH.sub.2 CN, CH.sub.2 CH.dbd.CH.sub.2, CH.sub.2 C.tbd.CH, CH.sub.2 CO.sub.2 (alkyl), CH.sub.2 OCH.sub.3, and NH.sub.2.
Preferred compounds are those of formula I where R is CH.sub.3, CH.sub.2 CH.sub.3, C(CH.sub.3).sub.2 OH, CH.sub.2 CH.sub.2 OH, CH(CH.sub.3).sub.2, t-butyl, CF.sub.3, CH(F)CH.sub.3, CF.sub.2 CF.sub.3, C(CH.sub.3).sub.2 OCOCH.sub.3, C(CH.sub.3).sub.2 NHSO.sub.2 CH.sub.3, CH.sub.2 CH.sub.2 CH.sub.2 C.tbd.N, CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3, and CON(CH.sub.3).sub.2 ; X is a chlorine, bromine or fluorine substituted in one or both of positions 4 and 6; J is ##STR5## and R.sup.3 is CH.sub.3 or NH.sub.2.
One aspect of the present invention relates to compounds of formula I in which A is nitrogen double-bonded to position 2 and B is oxygen, and R, R.sup.3, J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I in which A is oxygen and B is CR.sup.1 double bonded to position 2, and R, R.sup.1, R.sup.3, J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I in which A is NH and B is nitrogen double-bonded to position 2, and R, J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I in which A is nitrogen double bonded to position 2 and B is NR.sup.2,and R, R.sup.2, R.sup.3, J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I in which A is CH double bonded to position 2 and B is NR.sup.2, and R, R.sup.2, R.sup.3, J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I in which A is NH and B is CR.sup.1 double bonded to position 2, and R, R.sup.1, R.sup.3, J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I in which A and B are NH and R, R.sup.1, R.sup.3, J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I where J is not ##STR6## when: A is oxygen and B is CR.sup.1 double bonded to position 2; A is CH double bonded to position 2 and B is NR.sup.2 ; or A is NH and B is CR.sup.1 double bonded to position 2; and R, R.sup.1, R.sup.3, X, and n are as described above.
As shown in the specification a wide range of substituents is described for position B in compounds of formula I whereas position A is generally unsubstituted. It was found that some herbicidal activity is retained when a methyl substituent is placed at position A, but that substitution at that position generally causes a sharp decrease in activity.
Certain intermediates of the present invention are novel. These include compounds of formula II: ##STR7## where Y is NO.sub.2, NH.sub.2, or --NHN.dbd.C(CH.sub.3)R; Z is hydrogen, F, NH.sub.2, or OH; and R, J, X, and n are as described above; with the proviso that when Y is --NHN.dbd.C(CH.sub.3)R, Z is hydrogen.
As used in this specification and unless otherwise indicated, the terms "alkyl," "alkenyl," "alkynyl," "haloalkyl," and "alkoxy" used alone or as part of a larger moiety, includes straight or branched carbon chains of 1 to 6 carbon atoms. "Halogen" refers to fluorine, bromine or chlorine. "THF" means tetrahydrofuran, "DMF" means N,N-dimethylformamide, and "DBU" means 1,8-diazabicyclo[5.4.0]undec-7-ene. When "n" in is 2 or 3, the substituents X may be the same or different from one another.
SCHEME 1 ##STR8## a) 70% HNO.sub.3 /H.sub.2 SO.sub.4, 0-5.degree. C.; (b) NaOSi(CH.sub.3).sub.3, MeOH, dioxane; (c) Fe, EtOH, acetic acid, HCl, heat; (d) CF.sub.3 C(NH.sub.2).dbd.CO.sub.2 CH.sub.2 CH.sub.5, NaOSi(CH.sub.3).sub.3, DBU, DMF; (e) CH.sub.3 I, K.sub.2 CO.sub.3, DMF, 60-80.degree. C.; (f) HCl, NaNO.sub.2, Nal, H.sub.2 O; (g) BBr.sub.3, CH.sub.2 Cl.sub.2 ; (h) HC.tbd.CR,Pd(Ph.sub.3 P).sub.2 Cl.sub.2, Cul, triethylamine.
Benzofurans of formula I, where A is oxygen and B is CH double bonded to position 2, may be generally prepared as shown in Scheme 1. Starting with an appropriately substituted fluoroaniline derivative 1, nitration provides intermediate 2. Displacement of the fluorine of 2 with a methoxy group as shown in step b, followed by reduction of the nitro group as shown in step c provide the methoxyaniline 3. The methoxyaniline 3 is a versatile intermediate from which a number of compounds of the present invention can be made by attachment of various J groups. For example, a uracil ring may be appended as shown in step d to give intermediate 4a. At this point, R.sup.3 substituents other than H may be introduced, as shown for example in step e to provide 4b where R.sup.3 is methyl. Using diazotization conditions (step f) 4b is converted to the iodoanisole 5 which is then deprotected to give the iodophenol 6. Palladium-catalyzed acetylenic coupling and ring closure as shown in step h give benzofurans 7 of the present invention. To obtain benzofurans of formula I where the J group is other than uracil, approaches analogous to that outlined in Scheme 1 may be followed. Such approaches based on Scheme 1 would be known to one skilled in the art.
Scheme 2 ##STR9## a) 70% HNO.sub.3 /H.sub.2 SO.sub.4, 0-5.degree. C.; (b) Fe, aqueous acetic acid, 50.degree. C.; (c) RCOCl, pyridinium p-toluenesulfonate, triethylamine, xylene; (d) 1,1-carbonylimidazole, THF; (e) R'-halide, Ag.sub.2 O, CH.sub.2 Cl.sub.2 (to give 11 where R.dbd.R'O).
Benzoxazoles of formula I, where A is nitrogen double bonded to position 2 and B is oxygen, may be prepared as shown in Scheme 2 above. Starting with a phenol such as intermediate 8 nitration under standard conditions gives the nitrophenol 9. Certain of the benzoxazoles 11 of the present invention may be obtained by reduction of 9 to the aniline 10 followed by treatment with an acid halide (such as shown in step c). Alternatively, other benzoxazoles 11 may be obtained by treating 10 with carbonyldiimidazole to give intermediate 12 which can be O-alkyated according to step e. The approach outlined in Scheme 2 can be adapted, in ways known to one skilled in the art, to obtain benzoxazoles of formula I where the J group is other than uracil.
Scheme 3 ##STR10## a) see steps (d) and (e) of Scheme 1; (b) 70% HNO.sub.3 /H.sub.2 SO.sub.4, 0-5.degree. C.; (c) NH.sub.4 OAc, triethylamine, dioxane, heat; (d) SnCl.sub.2 H.sub.2 O or Fe, NH.sub.4 Cl, aqueous ethanol, heat; (e) RCO.sub.2 H, heat; RCO-halide, CH.sub.2 Cl.sub.2 /Pyridine, then POCl.sub.3, CH.sub.2 Cl.sub.2 ; alkoxycarbonyl isothiocyanate, HgCl.sub.2, heat (where R is --NHCO.sub.2 alkyl); or thiophosgene, EtOAC, heat (where R is --SH).
Benzimidazoles of formula I, where A is NH and B is nitrogen double bonded to position 2, may be prepared as shown in Scheme 3 above. For example, intermediate 13 may be converted to the uracil 14 by the well-known chemistry previously described. Nitration of 14 followed by aminolysis of the fluorine group (steps b and c) provides the nitroaniline 15. The diamine 16 is obtained by reduction of 15 under standard conditions. Benzimidazoles 17 of the present invention are obtained by treatment of 16 with a carboxylic acid, an acid halide, an alkoxycarbonyl isothiocyanate, or thiophosgene according to step e. Other benzimidazoles 17 of the present invention are obtained by derivativization of benzimidazoles depicted in Scheme 3 using techniques known to one skilled in the art. The approach outlined in Scheme 3 can be adapted, in ways known also to one skilled in the art, to obtain benzimidazoles of formula I where the J group is other than uracil. ##STR11##
Benzimidazoles of structure 17A where R.sup.3 is NH.sub.2 are prepared in a manner analogous to that depicted in Scheme 3, except the NH.sub.2 group is attached following nitration of the phenyl ring. The 1-unsubstituted uracil ring is formed as previously described in step d of Scheme 1, followed by nitration of the phenyl ring (Scheme 3, step b). The uracil ring is then aminated in the 1-position by methods known in the art by treating it with 1-aminooxysulfonyl-2,4,6-trimethylbenzene. The 1-aminouracil is then subjected to aminolysis of the phenyl fluorine (step c) followed by reduction to the diamine (step d). ##STR12##
2,3-Benzimidazoles of formula I, where A and B are NH may be prepared from Intermediate 16 in Scheme 3 by heating it with an appropriately substituted acetaldehyde ethyl hemiacetal, affording compounds of Structure 17B.
Scheme 4 ##STR13##
a) i. NaNO.sub.2, HCl; ii. SnCl.sub.2 2H.sub.2 O; iii. RCOCH.sub.3 ; (b) polyphosphoric acid, 80.degree. C.
Indoles of formula I, where A is CH double bonded to position 2 and B is NR.sup.1, may be prepared according to Scheme 4 above. Using a Fischer indole route the starting aniline 18 may be converted to the corresponding hydrazone 19 which in turn may be cyclized under acidic conditions such as is shown in step b. The resulting indoles 20 of the present invention may be further derivatized by alkylation of the indole ring nitrogen to indoles of formula I where R.sup.1 is other than hydrogen. The approach outlined in Scheme 4 can be adapted, in ways known to one skilled in the art, to obtain indoles of formula I where the J group is other than uracil. ##STR14##
Indoles of formula I, where A is NH and B is CR.sup.1 double bonded to position 2, may be prepared by a Fischer indole synthesis analogous to that shown in Scheme 4 starting with aniline 21. Substitution at the 3 position of indoles such as 22 with R.sup.1 groups is known to one skilled in the art.
Compounds of the present invention may also be prepared in accordance with the procedures shown in the Examples below, by procedures analogous to those shown in the Examples, or by other methods that are generally known or available to one skilled in the art.

EXAMPLE 1
1-Methyl-6-Trifluoromethyl-3-[7-Bromo-5-Fluoro-2-(2-Methylcarbonyloxyprop-2-yl)Benzoxazol-4-yl]-2,4(1H,3H)-Pyrimidinedione (Compound 104)
Step A 1-methyl-6-trifluoromethyl-3-(4-bromo-2-fluoro-5-hydroxy-6-nitrophenyl)-2,4(1H,3H)-pyrimidinedione
A stirred solution of 17.0 grams (0.044 mole) of 1-methyl-6-trifluoromethyl-3-(4-bromo-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione and 5.0 grams (0.050 mole) of sulfuric acid in 100 mL of glacial acetic acid was cooled to 15.degree. C., and 3.2 grams (0.050 mole) of 70% nitric acid was added dropwise. The reaction mixture was then allowed to warm to ambient temperature where it stirred for two hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 16.4 grams of title compound; mp 76-78.degree. C.
Step B 1-methyl-6-trifluoromethyl-3-(6-amino-4-bromo-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione
A stirred solution of 16.0 grams (0.037 mole) of 1-methyl-6-trifluoromethyl-3-(4-bromo-2-fluoro-5-hydroxy-6-nitrophenyl)-2,4(1H,3H)-pyrimidinedione and 10 mL of water in 120 mL of glacial acetic acid was heated to 50.degree. C., and 16.0 grams (excess) of iron dust was slowly added. The reaction mixture was then cooled to ambient temperature where it stirred for one hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was partitioned in a mixture of 150 mL portions each of water and ethyl acetate. The organic layer was separated, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 12.0 grams of title compound; mp 98-100.degree. C.
Step C Compound 104
A stirred solution of 0.50 gram (0.0013 mole) of 1-methyl-6-trifluoromethyl-3-(6-amino-4-bromo-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 0.21 gram (0.0013 mole) of 1-chlorocarbonyl-1-methylethyl acetate, 0.14 gram (0.0014 mole) of triethylamine, and 0.16 gram (0.0006 mole) of pyridinium p-toluenesulfonate in 50 mL of xylene was heated at 150 .degree. C. for about 18 hours. The reaction mixture was then cooled to ambient temperature and taken up in ethyl acetate. The solution was washed with water and an aqueous solution saturated with sodium chloride; then it was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 0.72 gram of Compound 104. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 2
1-Methyl-6-Trifluoromethyl-3-(7-Bromo-5-Fluoro-2-Methoxy-Benzoxazol-4-yl-2,4(1H,3H)-Pyrimidinedione (Compound 109)
Step A 1-methyl-6-trifluoromethyl-3-(7-bromo-5-fluorobenzoxazol-2-on-4-yl)-2,4(1H,3H)-pyrimidinedione
A stirred solution of 2.0 grams (0.005 mole) of 1-methyl-6-trifluoromethyl-3-(6-amino-4-bromo-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione and 1.2 grams (0.008 mole) of carbonylimidazole in 50 mL of THF was heated at reflux for three hours. The reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 1.1 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step B Compound 109
A mixture of 0.50 gram (0.001 mole) of 1-methyl-6-trifluoromethyl-3-(7-bromo-5-fluorobenzoxazol-2-on-4-yl)-2,4(1H,3H)-pyrimidinedione 0.17 gram (0.001 mole) of methyl iodode, and 0.27 gram (0.001 mole) of silver(l) oxide in 50 mL of methylene chloride was stirred at ambient temperature for two hours. The product was isolated from the reaction mixture by column chromatography on silica gel, yielding 0.28 gram of Compound 109. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 3
1-Methyl-6-Trifluoromethyl-3-[7-Chloro-5-Fluoro-2-(1-Methylethyl)Benzoxazol-4-yl]-2,4(1H,3H)-Pyrimidinedione (Compound 28)
Step A 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione
A stirred solution of 18.2 grams (0.054 mole) of 1-methyl-6-trifluoromethyl-3-(5-amino-4-chloro-2-fluorophenyl)-2,4(1H,3H)-pyrimidinedione in 100 mL of sulfuric acid was cooled to 5.degree. C., and a solution of 3.7 grams (0.054 mole) of sodium nitrite in about 10 mL of water was added dropwise. The reaction mixture was then warmed to ambient temperature where it stirred for two hours. In a separate reaction vessel, a stirred mixture of 242 grams (0.970 mole) of copper(II) sulfate and 1.5 grams (0.005 mole) of iron(II) sulfate heptahydrate in about 300 mL of water and 300 mL of xylene was heated to reflux, and the pyrimidinedione diazonium solution prepared above was added dropwise. The reaction mixture was stirred at reflux for two additional hours, then allowed to cool as it stirred for about 18 hours. The reaction mixture was poured into about 600 mL of water, and the aqueous/organic layers were separated. The aqueous layer was washed with ethyl acetate, and the wash was combined with the organic layer. The combined organic material was washed with water, then with an aqueous solution saturated with sodium chloride. The organic material was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding impure product. The product was dissolved in diethyl ether and washed with aqueous 10% hydrochloric acid, and with water. The diethyl ether solution was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 7.6 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step B 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5-hydroxy-6-nitrophenyl)-2,4(1H,3H)-pyrimidinedione
This compound was prepared in the manner of Step A of Example 1, using 3.8 grams (0.011 mole) of 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 1.0 gram (0.011 mole) of 70% nitric acid, and 50 mL of sulfuric acid, yielding 1.5 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step C 1-methyl-6-trifluoromethyl-3-(6-amino-4-chloro-2-fluoro-5-hydroxy-phenyl)-2,4(1H,3H)-pyrimidinedione
This compound was prepared in the manner of Step B of Example 1, using 1.5 grams (0.004 mole) 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5-hydroxy-6-nitrophenyl)-2,4(1H,3H)-pyrimidinedione, 3.0 grams (0.054 mole) of iron dust, and 5 mL of water in 50 mL of glacial acetic acid, yielding 1.0 gram of title compound. The NMR spectrum was consistent with the proposed structure.
Step D Compound 28
This compound was prepared in the manner of Step C of Example 1, using 0.52 gram (0.0015 mole) of 1-methyl-6-trifluoromethyl-3-(6-amino4-chloro-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 0.18 gram (0.0017 mole) of isobutyryl chloride, 0.24 gram (0.0017 mole) of triethylamine, and 0.09 gram (0.0004 mole) of pyridinium p-toluenesulfonate in 50 mL of xylene, yielding 0.22 gram of Compound 28. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 4
Synthesis of 3-(4-Chloro-6-Fluoro-2-Phenylbenzofuran-7-yl)-1-Methyl-6-Trifluoromethyl-2,4(1H,3H)-Pyrimidinedione (Compound 280)
Step A ethyl N-(4-chloro-2,6-difluoro-3-nitrophenyl)carbamate
A stirred solution of 23.6 grams (0.109 mole) of ethyl N-(4-chloro-2,6-difluorophenyl)carbamate in 125 mL of concentrated sulfuric acid was cooled to about 0.degree. C. and 7.7 mL (0.123 mole) of 70% nitric acid was added dropwise at a rate to maintain the reaction temperature below 10.degree. C. Upon completion of addition, the reaction mixture was stirred at 10.degree. C. for 30 minutes and then allowed to warm to ambient temperature where it stirred for about 18 hours. At the conclusion of this period, the reaction mixture was poured into 150 mL of ice-water. The resulting precipitate was collected by vacuum filtration and washed with water followed by petroleum ether. The precipitate was dried in a heated vacuum desicator, yielding 30.6 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step B ethyl N-(4-chloro-6-fluoro-2-methoxy-3-nitrophenyl)carbamate
Under a nitrogen atmosphere, a solution of 30.6 grams (0.109 mole) of ethyl N-(4-chloro-2,6-difluoro-3-nitrophenyl)carbamate and 18 mL (0.449 mole) of methanol in 175 mL of dioxane was stirred and 218 mL (0.218 mole) of 1 M sodium trimethylsilanoate (in tetrahydrofuran) was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was heated to 65.degree. C. where it stirred for three hours. At the conclusion of this period, the reaction mixture was allowed to cool to ambient temperature where it stirred for about 18 hours. The reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in cold 3 N hydrochloric acid. The resulting solid was collected by filtration, washed with petroleum ether, and heat dried under vacuum, yielding 21.3 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step C ethyl N-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)carbamate
Under a nitrogen atmosphere, a stirred solution of 21.3 grams (0.072 mole) of ethyl N-(4-chloro-6-fluoro-2-methoxy-3-nitrophenyl)carbamate, 18.3 grams (0.328 mole) of iron powder, 50 mL of acetic acid, and 250 mL of ethanol was heated to 65.degree. C. where it stirred for two hours. At the conclusion of this time, 3 mL (0.036 mole) of 12 M hydrochloric acid was added. Upon completion of addition, the reaction mixture was stirred for an additional two hours. After this time, the reaction mixture was concentrated under reduced pressure to yield a brown oil. The oil was then taken up in methylene chloride. The mixture was filtered through diatomaceous earth, and the filter cake was washed with water and an aqueous saturated sodium bicarbonate solution. The filtrate was stored over sodium sulfate for about 18 hours and then filtered. The solvent was removed under reduced pressure to yield a black oil. This oil was filtered through a silica gel pad, yielding 15.0 grams of ethyl N-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)carbamate. The NMR spectrum was consistent with the proposed structure.
Step D 3-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione
This compound was prepared using 4.0 grams (0.036 mole) of sodium trimethylsilanolate, 6.6 grams (0.036 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate, 8.5 grams (0.032 mole) of ethyl N-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)carbamate, and 2.2 grams (0.014 mole) of DBU in 75 mL of DMF. This preparation differs from well-known literature preparations for pyrimidinedione rings in that sodium trimethylsilanolate and DBU were used rather than sodium hydride. The yield of title compound was 1.7 grams. The NMR spectrum was consistent with the proposed structure.
Step E 3-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione
A solution of 7.5 grams (0.021 mole) of 3-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, 3.4 grams (0.025 mole) of potassium carbonate, and 3.5 grams (0.025 mole) of methyl iodide in 200 mL of acetone was stirred at ambient temperature for about 18 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in 200 mL of water. The mixture was extracted with two 100 mL portions of ethyl acetate. The combined extracts were washed with two 50 mL portions of an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 6.9 grams of crude product. The dark oil was combined with 7.0 grams of crude product prepared by a similar route to yield a total of 13.9 grams of crude product. The crude product was purified by column chromatography on silica gel, yielding 10.0 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step F 3-(4-chloro-6-fluoro-3-iodo-2-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione
A solution of 4.0 grams (0.011 mole) of 3-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione in 25 mL (0.300 mole) of concentrated hydrochloric acid was stirred and cooled in an ice bath. During a 15 minute period, 1.9 grams (0.013 mole) of sodium nitrite was added dropwise at a rate to maintain the reaction temperature at 15.degree. C. Upon completion of addition, the mixture was stirred for 20 minutes and then poured into 15.0 grams (0.090 mole) of potassium iodide. The reaction mixture was stirred for 30 minutes and then filtered. The filter cake was thoroughly washed with distilled water and then taken up in 150 mL of ethyl acetate. The resulting solution was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a brown solid. The solid was subjected to column chromatography on silica gel. Elution was accomplished using 5:1 heptane and ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.0 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step G 3-(4-chloro-6-fluoro-2-hydroxy-3-iodophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione
Under a nitrogen atmosphere, a stirred solution of 3.0 grams (0.006 mole) of 3-(4-chloro-6-fluoro-3-iodo-2-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1 H,3H)-pyrimidinedione in 75 mL of methylene chloride was cooled in a dry ice/acetone bath and 22.0 mL (0.022 mole) of 1 M boron tribromide (in methylene chloride) was added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature were it stirred for about one hour. At the conclusion of this period, the reaction mixture was poured into 200 mL of water and extracted with two 50 mL portions of methylene chloride. The combined extracts were washed with one 100 mL portion of an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 2.6 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step H Compound 280
Under a nitrogen atmosphere, a solution of 1.5 grams (0.003 mole) of 3-(4-chloro-6-fluoro-2-hydroxy-3-iodophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 0.41 gram (0.004 mole) of phenylacetylene, and 0.71 gram (0.007 mole) of triethylamine in 25 mL of DMF was stirred. To this was added 0.09 gram (0.00013 mole) of dichlorobis(triphenylphosphine)pallidium (II) and 0.05 gram (0.00026 mole) of copper (I) iodide. Upon completion of addition, the reaction mixture was heated to 70.degree. C. where it stirred for 2.5 hours. After this time, the reaction mixture was cooled to ambient temperature and then poured into 150 mL of an aqueous 10% ammonium chloride solution. The resulting precipitate was collected by filtration and washed with water. The precipitate was taken up in 120 mL of ethyl acetate. The resulting solution was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a brown solid. The solid was recrystallized using 1:1 chloroform and petroleum ether, yielding 0.31 gram of Compound 280. The mother liquor was concentrated to a residue. The residue was recrystallized using petroleum ether to yield an additional 0.21 gram of Compound 280, m.p. 215-216.degree. C. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 5
Synthesis of 3-(4-Chloro-6-Fluoro-2-Trifluoromethylbenzimidazol-7-yl)-1-Methyl-6-Trifluoromethyl-2,4(1H,3H)-Pyrimidinedione
(Compound 365)
A stirred solution of 3.0 grams (0.0085 mole) of 3-(5,6-diamino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 15.0 mL of trifluoroacetic acid was heated to 65.degree. C. where it stirred for one hour. At the conclusion of this period, the reaction mixture was analyzed by TLC, which indicated that the reaction was not complete. The reaction mixture was stirred at 65.degree. C. for an additional two hours. After this time, the reaction mixture was again analyzed by TLC, which indicated that the reaction was complete. The reaction mixture was allowed to cool to ambient temperature and then poured into 200 mL of water. The resulting mixture was allowed to stand at ambient temperature for about 18 hours. At the conclusion of this period, the resulting solid was collected by filtration and washed with water followed by heptane. The filter cake was dried under vacuum, yielding 3.6 grams of Compound 365, m.p. 130.degree. C. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 6
Synthesis of 3-(4-Chloro-2-Ethyl-6-Fluorobenzimidazol-7-yl)-1-Methyl-6-Trifluoromethyl-2,4(1H,3H)-Pyrimidinedione
(Compound 367)
Step A 3-(4-chloro-2,6-difluorophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione
Under a nitrogen atmosphere, a solution of 32.0 grams (0.900 mole) of sodium hydride (60% by weight) in 250 mL of DMF was vigorously stirred and cooled in an ice bath. To this a solution of 133.0 grams (0.726 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate in 150 mL of DMF was added dropwise at a rate to maintain the reaction mixture temperature at about 5.degree. C. Upon completion of addition, a solution of 156.3 grams (0.663 mole) of ethyl N-(4-chloro-2,6-difluorophenyl)carbamate in 250 mL of DMF was added dropwise. Upon completion of addition, the mixture was removed from the ice bath and heated to 130.degree. C. where it stirred for 3.5 hours. After this time, the mixture was analyzed by gas chromatography (GC), which indicated that only a slight amount of the starting material was left. The mixture was cooled to 5.degree. C. and 83.0 mL (1.333 moles) of methyl iodide was added dropwise at a rate to maintain the reaction mixture temperature below 20.degree. C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. At the conclusion of this period, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to yield a dark viscous oil. The oil was taken up in methylene chloride and washed with three 1000 mL portions of water followed by one 1000 mL portion of an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 223.8 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step B 3-(4-chloro-2,6-difluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione
A stirred solution of 211.0 grams (0.619 mole) of 3-(4-chloro-2,6-difluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 600 mL of concentrated sulfuric acid was cooled to less than 10.degree. C., and 44 mL (0.689 mole) of aqueous 70% nitric acid was added dropwise at a rate to maintain the reaction temperature below 10.degree. C. Upon completion of addition, the reaction mixture was analyzed by GC, which indicated the reaction was incomplete. The reaction was allowed to warm to ambient temperature and an additional 5 mL (0.078 mole) of aqueous 70% nitric acid was added. The reaction mixture was again analyzed by GC, which indicated the reaction was complete. The reaction mixture was poured into ice-water. The resulting solid was collected by filtration, washed with water, and then taken up in 600 mL of methylene chloride. The resulting solution was washed with two 600 mL portions of water, one 600 mL portion of an aqueous saturated sodium bicarbonate solution, and one 600 mL portion of an aqueous saturated sodium chloride solution. The organic layer was separated, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding a waxy tan solid. The solid was triturated with heptane and allowed to stand for about 72 hours. At the conclusion of this period, the solid was collected by filtration, washed with heptane, and dried under reduced pressure, yielding 201.4 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step C 3-(6-amino4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione
To stirred solution of 200 grams (0.519 mole) of 3-(4-chloro-2,6-difluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 1000 mL of dioxane was added 150 mL (1.091 moles) of triethylamine in one portion. Upon completion of addition, the mixture was vigorously stirred and 400 grams (5.189 moles) of ammonium acetate was added in one portion. The reaction mixture was heated to 90.degree. C. where it stirred for two hours. The reaction mixture was allowed to cool to ambient temperature where it stirred for about 18 hours. The resulting suspension was collected by filtration and washed with dioxane. The filtrate was concentrated under reduced pressure to yield a viscous dark oil. The oil was poured into ice-water. The resulting solid was collected by filtration and washed with water. The solid was dried under reduced pressure and then at ambient temperature for about 18 hours, yielding 195.1 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step D 3-(5,6-diamino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione and 3-(5,6-diamino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione
A solution of 278.0 grams (1.232.moles) of tin(II) chloride dihydrate, 264.0 grams (4.936 moles) of ammonium chloride, 400 mL of water. and 800 mL of ethanol was vigorously stirred, and 157.4 grams (0.411 mole) of 3-(6-amino-4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was added. Upon completion of addition, the reaction mixture was heated to 83-85.degree. C. where it stirred for 18 hours. After this time the reaction mixture was allowed to cool to ambient temperature. The resultant solid by-product was collected by filtration and washed with ethanol. The combined filtrate and wash was concentrated under reduced pressure to yield a suspension of additional by-product. The suspension was taken up in ethyl acetate and the resultant emulsion was filtered through a pad of diatomaceous earth. The filter cake was washed with ethyl acetate, and the combined organics were washed with three 200 mL portions of water. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a brown residue. The residue was triturated with heptane and allowed to stand for about five days. The resultant solid was collected by filtration and dried, yielding 144.4 grams of crude product. The crude product was combined with material prepared by a similar route, yielding a total of 157.8 grams of material. The combined product was subjected to column chromatography on silica gel, yielding 83.2 grams of an orange solid. The solid was slurried with warm ethyl acetate, and the insoluble product was collected by filtration. The product was washed with ethyl acetate, and the wash and filtrate from above were combined. The process of concentrating the filtrate, and slurrying the solid residue was repeated twice more, yielding a total of 51.9 grams of title compound. The NMR spectrum was consistent with the proposed structure.
An alternate method for preparing 3-(5,6-diamino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione is the following:
A solution of 19.2 grams (0.050 mole) of 3-(6-amino-4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 3.0 grams (0.056 mole) of ammonium chloride, and 50 mL of water in 100 mL of ethanol was stirred, and 11.2 grams (0.201 mole) of iron powder (325 mesh) was added in one portion. Upon completion of addition, the reaction mixture was heated at reflux for one hour. The reaction mixture was allowed to cool to ambient temperature, then it was filtered through diatomaceous earth to remove the iron powder. The filter cake was washed with 200 mL of acetone, and the wash was combined with the filtrate. The combination was stirred with decolorizing carbon and filtered. The filtrate was concentrated under reduced pressure, yielding a dark brown oil. The oil was then taken up in 200 mL of methylene chloride and washed with three 100 mL portions of an aqueous saturated sodium bicarbonate solution. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 12.8 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step E Compound 367
A stirred solution of 1.0 grams (0.0028 mole) of 3-(5,6-diamino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and 0.28 mL (0.0035 mole) of pyridine in 10 mL chloroform was cooled to 5.degree. C. and 0.27 mL (0.0031 mole) of propionyl chloride was added dropwise. Upon completion of addition, the mixture was allowed to warm to ambient temperature were it stirred for about 18 hours. The mixture was cooled to 5.degree. C. and 5.0 mL (0.054 mole) of phosphorous oxychloride was added in one portion. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. At the conclusion of this period, the reaction mixture was poured into 200 mL of cold water, the resulting mixture was stirred for one hour, then it was extracted with three 50 mL portions of chloroform. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.15 gram of an orange residue. The aqueous layer was made basic with an aqueous saturated sodium bicarbonate solution to a pH of 3-4. The resulting mixture was extracted with three 50 mL portions of methylene chloride. The extracts were combined, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 0.70 gram of a yellow residue. The yellow residue was triturated with hot heptane. The resulting solid was collected by filtration and washed with heptane, yielding 0.67 gram of Compound 367, m.p. 150-155.degree. C. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 7
Synthesis of 3-(2-t-Butyl-4-Chloro-6-Fluorobenzimidazol-7-yl)-1-Methyl-6-Trifluoromethyl-2,4(1H,3H)-Pyrimidinedione
(Compound 369)
To a stirred solution of 1.0 grams (0.0028 mole) of 3-(5,6-diamino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 15.0 mL of ethanol, and 4 mL of 5 M hydrochloric acid was added 1.2 mL (0.0057 mole) of 2,2,6,6-tetramethyl-3,5-heptanedione. Upon completion of addition, the reaction mixture was heated to reflux where it stirred for ten minutes. At the conclusion of this period, the reaction mixture was analyzed by TLC, which indicated that the reaction was not complete. The reaction mixture was stirred at reflux for an additional two hours. After this time, the reaction mixture was again analyzed by TLC, which again indicated that the reaction was still not complete. As a result, an additional 1.0 mL (0.0048 mole) of 2,2,6,6-tetramethyl-3,5-heptanedione was added. Upon completion of addition, the reaction mixture was stirred at reflux for three days. At the conclusion of this period, more ethanol was added to replace that which evaporated, and the reaction mixture was analyzed by TLC for a third time. The reaction mixture was allowed to cool to ambient temperature, poured into 100 mL of an aqueous saturated sodium bicarbonate solution, and 100 mL of chloroform was added. The aqueous layer was separated and washed with two 100 mL portions of chloroform. The chloroform layer and washes were combined, dried with magnesium sulfate, and filtered. The filtrate was treated with decolorizing carbon and stirred. The mixture was filtered and concentrated under reduced pressure to yield a red oil. The oil was taken up in heptane. The resulting solid was collected by filtration and washed with heptane to yield a tan solid. The solid was purified by column chromatography on silica gel, yielding 0.36 gram of Compound 369, m.p. 125-130.degree. C. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 8
Synthesis of 3-(7-Chloro-Fluoro-2-Trifluoromethylindol-4-yl)-1-Methyl-6-Trifluoromethyl-2,4(1H,3H)-Pyrimidinedione
(Compound 500)
Step A 3-[5-(1-trifluoromethylethylidenehydrazino)-4-chloro-2-fluorophenyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione
A solution of 3.37 grams (0.010 mole) of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 80 mL of concentrated hydrochloric acid was stirred at 25.degree. C. for 20 minutes. After this time, the solution was cooled to 10.degree. C. and a solution of 0.69 gram (0.010 mole) of sodium nitrite in 10 mL of water was slowly added. Upon completion of addition, the mixture was stirred for one hour at 10.degree. C. and then a solution of 5.64 grams (0.025 mole) of tin (II) chloride dihydrate in 40 mL of concentrated hydrochloric acid was slowly added. Upon completion of addition, the reaction mixture was warmed to 25.degree. C. where it stirred for one hour. At the conclusion of this period, 1.12 grams (0.010 mole) of trifluoroacetone was added and the resulting solid was collected by filtration, yielding 3.13 grams of title compound, m.p. 213-214.degree. C. The NMR spectrum was consistent with the proposed structure.
Step B Compound 500
A stirred solution of 2.0 grams (0.0044 mole) of 3-[5-(1-trifluoromethylethylidenehydrazino)-4-chloro-2-fluorophenyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 80 mL of polyphosphoric acid was heated at 80.degree. C. for 20 minutes. After this time, the reaction mixture was allowed to cool to 25.degree. C. where it was diluted with water. The resulting solid was collected by filtration, yielding 0.73 gram of Compound 500, m.p. 208-210.degree. C. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 9
Synthesis of 347-Chloro-2-Ethoxycarbonylindol4-yl)-4,5,6,7-Tetrahydro-1H-Isoindole-1,3(2H)-Dione
(Compound 595)
Step A 3-(1-ethoxycarbonylethylidenehydrazino)-4-chloronitrobenzene
This compound was prepared in the manner of Step A, Example 1, using, 17.25 grams (0.10 mole) of 2-chloro-5-nitroaniline, 6.9 grams (0.10 mole) of sodium nitrite, 56.4 grams (0.25 mole) of tin (II) chloride dihydrate, 11.61 grams (0.10 mole) of ethyl pyruvate, 30 mL of water, and 100 mL of concentrated hydrochloric acid. This preparation differs in that ethyl pyruvate was used rather than trifluoroacetone. The yield of title compound was 19.4 grams. The NMR spectrum was consistent with the proposed structure.
Step B 7-chloro-2-ethoxycarbonyl-4-nitroindole
This compound was prepared in the manner of Step B, Example 8, using 14.0 grams (0.050 mole) of 3-(1-ethoxycarbonylethylidenehydrazino)-4-chloronitrobenzene in 100 mL of polyphosphoric acid. The yield of title compound was 0.4 gram. The NMR spectrum was consistent with the proposed structure.
Step C 7-amino-4-chloro-2-ethoxycarbonylindole
A stirred solution of 2.68 grams (0.01 mole) of 4-chloro-2-ethoxycarbonyl-7-nitroindole, 80 mL of acetic acid, and 15 mL of water was heated to 65.degree. C., and 18.3 grams (0.048 mole) of iron powder was slowly added during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to cool to 25.degree. C. where it stirred for one hour. After this time, the reaction mixture was poured into water, and the resulting mixture was filtered through diatomaceous earth. The filter cake was washed thoroughly with ethyl acetate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure a residue. The residue was purified by column chromatography, yielding 0.4 gram of title compound. The NMR spectrum was consistent with the proposed structure.
Step D Compound 595
A stirred solution of 0.4 gram (0.0016 mole) of 7-amino-4-chloro-2-ethoxycarbonylindole and 0.26 gram (0.0016 mole) of 3,4,5,6-tetrahydrophhalic anhydride in 80 mL of acetic acid was heated at reflux for about 18 hours. After this time, the reaction mixture was extracted with several portions of diethyl ether. The organic extracts were combined, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 0.47 gram of Compound 595. The NMR spectrum was consistent with the proposed structure.
TABLE 1______________________________________Benzoxazoles ##STR15##where A is nitrogen double bonded to position 2 and B is O; J is ##STR16##Compound No. X R R3______________________________________1 4-Cl, 6-F CH.sub.3 CH.sub.32 4-Cl, 6-F CH.sub.3 C.sub.2 H.sub.53 4-Cl, 6-F CH.sub.3 CH.sub.2 CN4 4-Cl, 6-F CH.sub.3 CH.sub.2 CH.dbd.CH.sub.25 4-Cl, 6-F CH.sub.3 NH.sub.26 4-Cl, 6-F CH.sub.3 CH.sub.2 C.tbd.CH7 4-Cl, 6-F CH.sub.3 C.sub.3 H.sub.78 4-Cl, 6-F CH.sub.3 CH.sub.2 OCH.sub.39 4-Cl, 6-F CH.sub.3 CH.sub.2 CO.sub.2 C.sub.2 H.sub.5______________________________________
TABLE 2__________________________________________________________________________ ##STR17## ##STR18## ##STR19## ##STR20## ##STR21## Double BondNo. A B Posit'n X R J__________________________________________________________________________ 10 N O 1-2 4-Cl CH.sub.3 J1 11 N O 1-2 4-Cl C.sub.2 H.sub.5 J1 12 N O 1-2 4-Cl CH(CH.sub.3).sub.2 J1 13 N O 1-2 4,6-Cl.sub.2 CH.sub.3 J1 14 N O 1-2 4,6-Cl.sub.2 C.sub.2 H.sub.5 J1 15 N O 1-2 4,6-Cl.sub.2 C.sub.2 H.sub.5 J1 16 N O 1-2 4-Br, 6-F CH.sub.3 J1 17 N O 1-2 4-CF.sub.3, 6-F CH.sub.3 J1 18 N O 1-2 4,6-F.sub.2 CH.sub.3 J1 19 N O 1-2 4-CN, 6-F CH.sub.3 J1 20 N O 1-2 4-OCF.sub.3, 6-F CH.sub.3 J1 21 N O 1-2 4-Br, 6-F C.sub.2 H.sub.5 J1 22 N O 1-2 4-CN, 6-F C.sub.2 H.sub.5 J1 23 N O 1-2 4-CN, 6-F CH(CH.sub.3).sub.2 J1 24 N O 1-2 4-CH.sub.3, 6-F CH.sub.3 J1 25 N O 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1 26 N O 1-2 4-Cl, 6-F C.sub.3 H.sub.7 J1 27 N O 1-2 4-Cl, 6-F C.sub.4 H.sub.9 J1 28 N O 1-2 4-Cl, 6-F CH(CH.sub.3).sub.2 J1 29 N O 1-2 4-Cl, 6-F CH.sub.2 CH(CH.sub.3).sub.2 J1 30 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.3 J1 31 N O 1-2 4-Cl, 6-F phenyl J1 32 N O 1-2 4-Cl, 6-F phenylmethyl J1 33 N O 1-2 4-Cl, 6-F CF.sub.3 J1 34 N O 1-2 4-Cl, 6-F CCl.sub.2 J1 35 N O 1-2 4-Cl, 6-F Cl J1 36 N O 1-2 4-Cl, 6-F OH J1 37 N O 1-2 4-Cl, 6-F Br J1 38 N O 1-2 4-Cl, 6-F NH.sub.2 J1 39 N O 1-2 4-Cl, 6-F NHCH.sub.3 J1 40 N O 1-2 4-Cl, 6-F N(CH.sub.3).sub.2 J1 41 N O 1-2 4-Cl, 6-F NHCH.sub.2 CO.sub.2 CH.sub.3 J1 42 N O 1-2 4-Cl, 6-F NHSO.sub.2 CH.sub.3 J1 43 N O 1-2 4-Br, 6-F NHCOCH.sub.3 J1 44 N O 1-2 4-Cl, 6-F morpholino J1 45 N O 1-2 4-Cl, 6-F NHSO.sub.2 C.sub.6 H.sub.5 J1 46 N O 1-2 4-Cl, 6-F NHSO.sub.2 CH.sub.2 C.sub.6 H.sub.5 J1 47 N O 1-2 4-Cl, 6-F N(CH.sub.3)SO.sub.2 CH.sub.3 J1 48 N O 1-2 4-Cl, 6-F NHPO(OCH.sub.3).sub.2 J1 49 N O 1-2 4-Br, 6-F CH.sub.2 CO.sub.2 CH.sub.3 J1 50 N O 1-2 4-Cl, 6-F C.sub.2 H.sub.4 CO.sub.2 CH.sub.3 J1 51 N O 1-2 4-Cl, 6-F CH.dbd.CHCO.sub.2 CH.sub.3 J1 52 N O 1-2 4-Cl, 6-F CH.dbd.C(Cl)CO.sub.2 CH.sub.3 J1 53 N O 1-2 4-Cl, 6-F CH.sub.2 CH(Cl)CO.sub.2 CH.sub.3 J1 54 N O 1-2 4-Cl, 6-F OCH.sub.3 J1 55 N O 1-2 4-Cl, 6-F OC.sub.2 H.sub.5 J1 56 N O 1-2 4-Cl, 6-F OCH(CH.sub.3).sub.2 J1 57 N O 1-2 4-Cl, 6-F OCH.sub.2 CH.dbd.CH.sub.2 J1 58 N O 1-2 4-Cl, 6-F OCH.sub.2 C(CH.sub.3).dbd.CH.sub.2 J1 59 N O 1-2 4-Cl, 6-F OCH.sub.2 CCH J1 60 N O 1-2 4-Cl, 6-F OCH.sub.2 CO.sub.2 C.sub.2 H.sub.5 J1 61 N O 1-2 4-Cl, 6-F OCH(CH.sub.3)CO.sub.2 CH.sub.3 J1 62 N O 1-2 4-Cl, 6-F OCH.sub.2 CN J1 63 N O 1-2 4-Cl, 6-F OCH.sub.2 CONH.sub.2 J1 64 N O 1-2 4-Cl, 6-F OCH.sub.2 CONHCH.sub.3 J1 65 N O 1-2 4-Cl, 6-F OCH(CH.sub.3)CONH.sub.2 J1 66 N O 1-2 4-Cl, 6-F OCH(CH.sub.3)CONHCH.sub.3 J1 67 N O 1-2 4-Cl, 6-F OCH.sub.2 CO.sub.2 H J1 68 N O 1-2 4-Cl, 6-F phenoxy J1 69 N O 1-2 4-Cl, 6-F p-OC.sub.6 H.sub.4 OCH(CH.sub.3)CO.sub.2 CH.sub.3 J1 70 N O 1-2 4-Cl, 6-F 4-chlorophenoxy J1 71 N O 1-2 4-Cl, 6-F phenylmethoxy J1 72 N O 1-2 4-Cl, 6-F CN J1 73 N O 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1 74 N O 1-2 4-Cl, 6-F CO.sub.2 H J1 75 N O 1-2 4-Cl, 6-F CO.sub.2 Na J1 76 N O 1-2 4-Cl, 6-F CONH.sub.2 J1 77 N O 1-2 4-Cl, 6-F CONHCH.sub.3 J1 78 N O 1-2 4-Cl, 6-F CON(CH.sub.3).sub.2 J1 79 N O 1-2 4-Cl, 6-F CONHSO.sub.2 CH.sub.3 J1 80 N O 1-2 4-Cl, 6-F CO.sub.2 NHOCH.sub.3 J1 81 N O 1-2 4-Cl, 6-F SCH.sub.3 J1 82 N O 1-2 4-Cl, 6-F SCH.sub.2 CO.sub.2 CH.sub.3 J1 83 N O 1-2 4-Cl, 6-F SCH.sub.2 CONH.sub.2 J1 84 N O 1-2 4-Cl, 6-F SO.sub.2 CH.sub.3 J1 85 N O 1-2 4-Cl, 6-F SH J1 86 N O 1-2 4-Cl, 6-F CH.sub.2 OH J1 87 N O 1-2 4-Cl, 6-F CH(CH.sub.3)OH J1 88 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OH J1 89 N O 1-2 4-Cl, 6-F C.sub.2 H.sub.4 OH J1 90 N O 1-2 4-Cl, 6-F CH.sub.2 CH(CH.sub.3)OH J1 91 N O 1-2 4-Cl, 6-F CH.sub.2 C(CH.sub.3).sub.2 OH J1 92 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OCOCH.sub.3 J1 93 N O 1-2 4-Cl, 6-F CH(CH.sub.3).sub.2 OCOCH.sub.3 J1 94 N O 1-2 4-Cl, 6-F CH(CH.sub.3)OCOCH.sub.3 J1 95 N O 1-2 4-Cl, 6-F CHBr.sub.2 J1 96 N O 1-2 4-Br, 6-F CH.sub.2 OCH.sub.3 J1 97 N O 1-2 4-Cl, 6-F CH.sub.2 OCH.sub.2 CCH J1 98 N O 1-2 4-Br, 6-F NH.sub.2 J1 99 N O 1-2 4-Br, 6-F phenoxymethyl J1100 N O 1-2 4-Br, 6-F N(COCH.sub.3).sub.2 J1101 N O 1-2 4-Br, 6-F CH.sub.2 OCOCH.sub.3 J1102 N O 1-2 4-Br, 6-F 4-chlorophenoxymethyl J1103 N O 1-2 4-Br, 6-F CH(Ph)OCOCH.sub.3 J1104 N O 1-2 4-Br, 6-F C(CH.sub.3).sub.2 OCOCH.sub.3 J1105 N O 1-2 4-Br, 6-F CO.sub.2 H J1106 N O 1-2 4-Br, 6-F OCH.sub.2 CCH J1107 N O 1-2 4-Br, 6-F OCH(CH.sub.3).sub.2 J1108 N O 1-2 4-Br, 6-F NHSO.sub.2 CH.sub.3 J1109 N O 1-2 4-Br, 6-F OCH.sub.3 J1110 N O 1-2 4-Br, 6-F OCH.sub.2 CH.dbd.CH.sub.2 J1111 N O 1-2 4-Cl, 6-F (CH.sub.3)(CN)OH J1112 N O 1-2 4-Cl, 6-F CH.sub.3 J2113 N O 1-2 4-Cl, 6-F n-C.sub.3 H.sub.7 J2114 N O 1-2 4-Cl, 6-F i-C.sub.3 H.sub.7 J2115 N O 1-2 4-Cl, 6-F t-C.sub.4 H.sub.9 J2116 N O 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J2117 N O 1-2 4-Cl, 6-F CH.sub.2 CO.sub.2 CH.sub.3 J2118 N O 1-2 4-Cl, 6-F phenoxymethyl J2119 N O 1-2 4-Cl, 6-F CONHCH.sub.3 J2120 N O 1-2 4-Cl, 6-F CON(CH.sub.3).sub.2 J2121 N O 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J2122 N O 1-2 4-Cl, 6-F Phenyl J2123 N O 1-2 4-Cl, 6-F SCH.sub.3 J2124 N O 1-2 4-Cl, 6-F CH.sub.2 OCH.sub.3 J2125 N O 1-2 4-Cl, 6-F Benzyl J2126 N O 1-2 4-Cl, 6-F 4-chlorophenylmethyl J2127 N O 1-2 4-Cl, 6-F SO.sub.2 CH.sub.3 J2128 N O 1-2 4-Cl, 6-F CF.sub.3 J2129 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OCO.sub.2 CH.sub.3 J2130 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OH J2131 N O 1-2 4-Cl, 6-F CH.sub.3 J3132 N O 1-2 4-Cl, 6-F n-C.sub.3 H.sub.7 J3133 N O 1-2 4-Cl, 6-F i-C.sub.3 H.sub.7 J3134 N O 1-2 4-Cl, 6-F t-C.sub.4 H.sub.9 J3135 N O 1-2 4-Cl, 6-F CH.sub.2 OH J3136 N O 1-2 4-Cl, 6-F CH.sub.2 CH.sub.2 OH J3137 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OH J3138 N O 1-2 4-Cl, 6-F CONHCH.sub.3 J3139 N O 1-2 4-Cl, 6-F CON(CH.sub.3).sub.2 J3140 N O 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J3141 N O 1-2 4-Cl, 6-F Phenyl J3142 N O 1-2 4-Cl, 6-F SCH.sub.3 J3143 N O 1-2 4-Cl, 6-F CH.sub.2 OCH.sub.3 J3144 N O 1-2 4-Cl, 6-F Benzyl J3145 N O 1-2 4-Cl, 6-F 4-chlorophenylmethyl J3146 N O 1-2 4-Cl, 6-F SO.sub.2 CH.sub.3 J3147 N O 1-2 4-Cl, 6-F CF.sub.3 J3148 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OCO.sub.2 CH.sub.3 J3149 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OH J3150 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OCH.sub.3 J3151 N O 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J3152 N O 1-2 4-Cl, 6-F CO.sub.2 Na J3153 N O 1-2 4-Cl, 6-F CONHSO.sub.2 CH.sub.3 J3154 N O 1-2 4-Cl, 6-F OCH.sub.2 CO.sub.2 CH.sub.3 J3155 N O 1-2 4-Cl, 6-F OCH(CH.sub.3)CO.sub.2 CH.sub.3 J3156 N O 1-2 4-Cl, 6-F OCH.sub.2 CH.dbd.CH.sub.2 J3157 N O 1-2 4-Cl, 6-F OCH.sub.2 CCH J3158 N O 1-2 4-Cl, 6-F OH J3159 N O 1-2 4-Cl, 6-F OCH.sub.3 J3160 N O 1-2 4-Cl, 6-F OCH(CH.sub.3).sub.2 J3161 N O 1-2 4-Cl, 6-F CH.sub.3 J4162 N O 1-2 4-Cl, 6-F n-C.sub.3 H.sub.7 J4163 N O 1-2 4-Cl, 6-F i-C.sub.3 H.sub.7 J4164 N O 1-2 4-Cl, 6-F t-C.sub.4 H.sub.9 J4165 N O 1-2 4-Cl, 6-F CH.sub.2 OH J4166 N O 1-2 4-Cl, 6-F CH.sub.2 CH.sub.2 OH J4167 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OH J4168 N O 1-2 4-Cl, 6-F CONHCH.sub.3 J4169 N O 1-2 4-Cl, 6-F CON(CH.sub.3).sub.2 J4170 N O 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J4171 N O 1-2 4-Cl, 6-F Phenyl J4172 N O 1-2 4-Cl, 6-F SCH.sub.3 J4173 N O 1-2 4-Cl, 6-F CH.sub.2 OCH.sub.3 J4174 N O 1-2 4-Cl, 6-F Benzyl J4175 N O 1-2 4-Cl, 6-F 4-chlorophenylmethyl J4176 N O 1-2 4-Cl, 6-F SO.sub.2 CH.sub.3 J4177 N O 1-2 4-Cl, 6-F CF.sub.3 J4178 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OCO.sub.2 CH.sub.3 J4179 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OH J4180 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OCH.sub.3 J4181 N O 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J4182 N O 1-2 4-Cl, 6-F CO.sub.2 Na J4183 N O 1-2 4-Cl, 6-F CONHSO.sub.2 CH.sub.3 J4184 N O 1-2 4-Cl, 6-F OCH.sub.2 CO.sub.2 CH.sub.3 J4185 N O 1-2 4-Cl, 6-F OCH(CH.sub.3)CO.sub.2 CH.sub.3 J4186 N O 1-2 4-Cl, 6-F OCH.sub.2 CH.dbd.CH.sub.2 J4187 N O 1-2 4-Cl, 6-F OCH.sub.2 C.tbd.CH J4188 N O 1-2 4-Cl, 6-F OH J4189 N O 1-2 4-Cl, 6-F OCH.sub.3 J4190 N O 1-2 4-Cl, 6-F OCH(CH.sub.3).sub.2 J4191 N O 1-2 4-Cl, 6-F CH.sub.3 J5192 N O 1-2 4-Cl, 6-F n-C.sub.3 H.sub.7 J5193 N O 1-2 4-Cl, 6-F i-C.sub.3 H.sub.7 J5194 N O 1-2 4-Cl, 6-F t-C.sub.4 H.sub.9 J5195 N O 1-2 4-Cl, 6-F CH.sub.2 OH J5196 N O 1-2 4-Cl, 6-F CH.sub.2 CH.sub.2 OH J5197 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OH J5198 N O 1-2 4-Cl, 6-F CONHCH.sub.3 J5199 N O 1-2 4-Cl, 6-F CON(CH.sub.3).sub.2 J5200 N O 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J5201 N O 1-2 4-Cl, 6-F Phenyl J5202 N O 1-2 4-Cl, 6-F SCH.sub.3 J5203 N O 1-2 4-Cl, 6-F CH.sub.2 OCH.sub.3 J5204 N O 1-2 4-Cl, 6-F Benzyl J5205 N O 1-2 4-Cl, 6-F 4-chlorophenylmethyl J5206 N O 1-2 4-Cl, 6-F SO.sub.2 CH.sub.3 J5207 N O 1-2 4-Cl, 6-F CF.sub.3 J5208 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OCO.sub.2 CH.sub.3 J5209 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OH J5210 N O 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OCH.sub.3 J5211 N O 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J5212 N O 1-2 4-Cl, 6-F CO.sub.2 Na J5213 N O 1-2 4-Cl, 6-F CONHSO.sub.2 CH.sub.3 J5214 N O 1-2 4-Cl, 6-F OCH.sub.2 CO.sub.2 CH.sub.3 J5215 N O 1-2 4-Cl, 6-F OCH(CH.sub.3)CO.sub.2 CH.sub.3 J5216 N O 1-2 4-Cl, 6-F OCH.sub.2 CH.dbd.CH.sub.2 J5217 N O 1-2 4-Cl, 6-F OCH.sub.2 CCH J5218 N O 1-2 4-Cl, 6-F OH J5219 N O 1-2 4-Cl, 6-F OCH.sub.3 J5220 N O 1-2 4-Cl, 6-F OCH(CH.sub.3).sub.2 J5221 O CH 2-3 4-Cl CH.sub.3 J1222 O CH 2-3 4-Cl, 6-F CH.sub.3 J1223 O CH 2-3 4-Cl, 6-F n-propyl J1224 O CH 2-3 4-Cl, 6-F isopropyl J1225 O CH 2-3 4-Cl n-butyl J1226 O CH 2-3 4-Cl t-butyl J1227 O CH 2-3 4-Cl, 6-F t-butyl J1228 O CH 2-3 4,6-F.sub.2 t-butyl J1229 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)C.sub.3 H.sub.7 J1230 O CH 2-3 4-Cl, 6-F CH.dbd.CH.sub.2 J1231 O CH 2-3 4-Cl, 6-F C(CH.sub.3).dbd.CH.sub.2 J1232 O CH 2-3 4-Cl CH.sub.2 Br J1233 O CH 2-3 4-Cl CHBr.sub.2 J1234 O CH 2-3 4-Cl, 6-F CH(Cl)CH.sub.3 J1235 O CH 2-3 4-Cl, 6-F CH(F)CH.sub.3 J1236 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 Cl J1237 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 F J1238 O CH 2-3 4-Cl CH.sub.2 OH J1239 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 OH J1240 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OH J1241 O CH 2-3 4-Cl C(CH.sub.3).sub.2 OH J1242 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OH J1243 O CH 2-3 4-Cl, 6-F CH.sub.2 CH(CH.sub.3)OH J1244 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OC(CH.sub.3).sub.3 J1245 O CH 2-3 4-Cl, 6-F CH(OC.sub.2 H.sub.5).sub.2 J1246 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OCOCH.sub.3 J1247 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OCOCH(CH.sub.3).sub.2 J1248 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OCOPh J1249 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OCONHCH.sub.3 J1250 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OCONHCH.sub.2 Ph J1251 O CH 2-3 4-Cl C(CH.sub.3).sub.2 OCH.sub.3 J1252 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OCH.sub.2 OCH.sub.3 J1253 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OCOCH.sub.3 J1254 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 NH.sub.2 J1255 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 NHSO.sub.2 CH.sub.3 J1256 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CH.sub.2 CN J1257 O CH 2-3 4-Cl CH.sub.2 N(C.sub.2 H.sub.5).sub.2 J1258 O CH 2-3 4-Cl CH.dbd.NOH J1259 O CH 2-3 4-Cl CH.dbd.NOCH.sub.3 J1260 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 OCOCH.sub.3 J1261 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 OCONHCH.sub.3 J1262 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CO.sub.2 H J1263 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3 J1264 O CH 2-3 4-Cl Phenyl J1265 O CH 2-3 4-Cl CHO J1266 O CH 2-3 4-Cl CO.sub.2 H J1267 O CH 2-3 H CO.sub.2 C.sub.2 H.sub.5 J1268 O CH 2-3 4-Cl CO.sub.2 C.sub.2 H.sub.5 J1269 O CH 2-3 4-Cl CONH.sub.2 J1270 O CH 2-3 4-Cl CONHCH.sub.3 J1271 O CH 2-3 4-Cl CON(CH.sub.3).sub.2 J1272 O CH 2-3 4-Cl NHCO.sub.2 C(CH.sub.3).sub.3 J1273 O CH 2-3 4-Cl, 6-F CONH.sub.2 J1274 O CH 2-3 4-Cl, 6-F CONH(CH.sub.3) J1275 O CH 2-3 4-Cl, 6-F CON(CH.sub.3).sub.2 J1276 O CH 2-3 4-Cl, 6-F CO.sub.2 H J1277 O CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J1278 O CH 2-3 4-Cl, 6-F CH.sub.2 OH J1279 O CH 2-3 4-Cl, 6-F 3,4-dimethoxyphenyl J1280 O CH 2-3 4-Cl, 6-F Phenyl J1281 O CH 2-3 4-Cl, 6-F CH.sub.3 J2282 O CH 2-3 4-Cl, 6-F n-propyl J2283 O CH 2-3 4-Cl, 6-F isopropyl J2284 O CH 2-3 4-Cl, 6-F t-butyl J2285 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)C.sub.3 H.sub.7 J2286 O CH 2-3 4-Cl, 6-F CH.dbd.CH.sub.2 J2287 O CH 2-3 4-Cl, 6-F C(CH.sub.3).dbd.CH.sub.2 J2288 O CH 2-3 4-Cl, 6-F CH(Cl)CH.sub.3 J2289 O CH 2-3 4-Cl, 6-F CH(F)CH.sub.3 J2290 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 Cl J2291 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 F J2292 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 OH J2293 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OH J2294 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OH J2295 O CH 2-3 4-Cl, 6-F CH.sub.2 CH(CH.sub.3)OH J2296 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OC(CH.sub.3).sub.3 J2297 O CH 2-3 4-Cl, 6-F CH(OC.sub.2 H.sub.5).sub.2 J2298 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OCOCH.sub.3 J2299 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OCOCH(CH.sub.3).sub.2 J2300 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OCOPh J2301 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OCONHCH.sub.3 J2302 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OCONHCH.sub.2 Ph J2303 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OCH.sub.2 OCH.sub.3 J2304 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OCOCH.sub.3 J2305 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 NH.sub.2 J2306 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 NHSO.sub.2 CH.sub.3 J2307 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CH.sub.2 CN J2308 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 OCOCH.sub.3 J2309 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 OCONHCH.sub.3 J2310 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CO.sub.2 H J2311 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3 J2312 O CH 2-3 4-Cl, 6-F CONH.sub.2 J2313 O CH 2-3 4-Cl, 6-F CONH(CH.sub.3) J2314 O CH 2-3 4-Cl, 6-F CON(CH.sub.3).sub.2 J2315 O CH 2-3 4-Cl, 6-F CO.sub.2 H J2316 O CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J2317 O CH 2-3 4-Cl, 6-F CH.sub.2 OH J2318 O CH 2-3 4-Cl, 6-F 3,4-dimethoxyphenyl J2319 O CH 2-3 4-Cl, 6-F Phenyl J2320 O CH 2-3 4-Cl, 6-F CH.sub.3 J3321 O CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J3322 O CH 2-3 4-Cl, 6-F CH(Cl)CH.sub.3 J3323 O CH 2-3 4-Cl, 6-F CH(F)CH.sub.3 J3324 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 Cl J3325 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 F J3326 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 OH J3327 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OH J3328 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OH J3329 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OCH.sub.2 OCH.sub.3 J3330 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 NHSO.sub.2 CH.sub.3 J3331 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CH.sub.2 CN J3332 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3 J3333 O CH 2-3 4-Cl, 6-F CON(CH.sub.3).sub.2 J3334 O CH 2-3 4-Cl, 6-F CH.sub.3 J4335 O CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J4336 O CH 2-3 4-Cl, 6-F CH(Cl)CH.sub.3 J4337 O CH 2-3 4-Cl, 6-F CH(F)CH.sub.3 J4338 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 Cl J4339 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 F J4340 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 OH J4341 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OH J4342 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OH J4343 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OCH.sub.2 OCH.sub.3 J4344 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 NHSO.sub.2 CH.sub.3 J4345 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CH.sub.2 CN J4346 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3 J4347 O CH 2-3 4-Cl, 6-F CON(CH.sub.3).sub.2 J4348 O CH 2-3 4-Cl, 6-F CH.sub.3 J5349 O CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J5350 O CH 2-3 4-Cl, 6-F CH(Cl)CH.sub.3 J5351 O CH 2-3 4-Cl, 6-F CH(F)CH.sub.3 J5352 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 Cl J5353 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 F J5354 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 OH J5355 O CH 2-3 4-Cl, 6-F CH(CH.sub.3)OH J5356 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OH J5357 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OCH.sub.2 OCH.sub.3 J5358 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 NHSO.sub.2 CH.sub.3 J5359 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CH.sub.2 CN J5360 O CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3 J5361 O CH 2-3 4-Cl, 6-F CON(CH.sub.3).sub.2 J5362 NH N 2-3 4-Cl, 6-F H J1363 NH N 2-3 4-Cl, 6-F CH.sub.3 J1364 NH N 2-3 4-Cl, 6-F CHF.sub.2 J1365 NH N 2-3 4-Cl, 6-F CF.sub.3 J1366 NH N 2-3 4-Cl, 6-F CClF.sub.2 J1367 NH N 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J1368 NH N 2-3 4-Cl, 6-F i-C.sub.3 H.sub.7 J1369 NH N 2-3 4-Cl, 6-F t-C.sub.4 H.sub.9 J1370 NH N 2-3 4-Cl, 6-F CH.sub.2 OCH.sub.3 J1371 NH N 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OC(O)CH.sub.3 J1372 NH N 2-3 4-Cl, 6-F C.sub.2 H.sub.4 CO.sub.2 C.sub.2 H.sub.5 J1373 NH N 2-3 4-Cl, 6-F Cyclohexyl J1374 NH N 2-3 4-Cl, 6-F Adamantyl J1375 NH N 2-3 4-Cl, 6-F Phenyl J1376 NH N 2-3 4-Cl, 6-F Benzyl J1377 NH N 2-3 4-Cl, 6-F CH(CH.sub.3)C.sub.6 H.sub.5 J1378 NH N 2-3 4-Cl, 6-F CH.sub.2 OC.sub.6 H.sub.5 J1379 NH N 2-3 4-Cl, 6-F C.sub.2 H.sub.4 C.sub.8 H.sub.5 J1380 NH N 2-3 4-Cl, 6-F C.sub.3 H.sub.6 C.sub.6 H.sub.5 J1381 NH N 2-3 4-Cl, 6-F 2-chlorophenylmethyl J1382 NH N 2-3 4-Cl, 6-F 3-chlorophenylmethyl J1383 NH N 2-3 4-Cl, 6-F 4-chlorophenylmethyl J1384 NH N 2-3 4-Cl, 6-F CF.sub.2 CF.sub.3 J1385 NH N 2-3 4-Cl, 6-F Furan-2-yl J1386 NH N 2-3 4-Cl, 6-F CH.sub.2 Cl J1387 NH N 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 Cl J1388 NH N 2-3 4-Cl, 6-F OC.sub.2 H.sub.5 J1389 N NH 1-2 4-Cl, 6-F CH.sub.3 J1390 N NH 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1391 N NH 1-2 4-Cl, 6-F isopropyl J1392 N NH 1-2 4-Cl, 6-F t-butyl J1393 N NH 1-2 4-Cl, 6-F CF.sub.3 J1394 N NH 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1395 N NCH.sub.3 1-2 4-Cl, 6-F CH.sub.3 J1396 N NCH.sub.3 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1397 N NCH.sub.3 1-2 4-Cl, 6-F isopropyl J1398 N NCH.sub.3 1-2 4-Cl, 6-F t-butyl J1399 N NCH.sub.3 1-2 4-Cl, 6-F CF.sub.3 J1400 N NCH.sub.3 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1401 N NCH.sub.3 1-2 4-Cl, 6-F CO.sub.2 CH.sub.2 CH.sub.3 J1402 N NC.sub.2 H.sub.5 1-2 4-Cl, 6-F CH.sub.3 J1403 N NC.sub.2 H.sub.5 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1404 NH NH -- 4-NO.sub.2, 6-F CF.sub.3 J1405 N.sup.- H.sub.3 N.sup.+ CH(CH.sub.3).sub.2 N 2-3 4-Cl, 6-F CH.sub.3 J1406 NCH.sub.3 N 2-3 4-Cl, 6-F CF.sub.3 J1407 NCH.sub.3 NC.sub.2 H.sub.5 1-2 4-Cl, 6-F isopropyl J1408 N NC.sub.2 H.sub.5 1-2 4-Cl, 6-F t-butyl J1409 N NC.sub.2 H.sub.5 1-2 4-Cl, 6-F CF.sub.3 J1410 N NC.sub.2 H.sub.5 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1411 N NC.sub.4 H.sub.9 1-2 4-Cl, 6-F CH.sub.3 J1412 N NC.sub.4 H.sub.9 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1413 N NC.sub.4 H.sub.9 1-2 4-Cl, 6-F isopropyl J1414 N NC.sub.4 H.sub.9 1-2 4-Cl, 6-F t-butyl J1415 N NC.sub.4 H.sub.9 1-2 4-Cl, 6-F CF.sub.3 J1416 N NC.sub.4 H.sub.9 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1417 N NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F CH.sub.3 J1418 N NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1419 N NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F isopropyl J1420 N NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F t-butyl J1421 N NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F CF.sub.3 J1422 N NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1423 N NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CH.sub.3 J1424 N NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1425 N NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F isopropyl J1426 N NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F t-butyl J1427 N NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CF.sub.3 J1428 N NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1429 N NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CH.sub.3 J1430 N NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1431 N NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F isopropyl J1432 N NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F t-butyl J1433 N NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CF.sub.3 J1434 N NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1435 N NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F CH.sub.3 J1436 N NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1437 N NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F isopropyl J1438 N NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F t-butyl J1439 N NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F CF.sub.3 J1440 N NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1441 N NCH.sub.2 CCH 1-2 4-Cl, 6-F CH.sub.3 J1442 N NCH.sub.2 CCH 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1443 N NCH.sub.2 CCH 1-2 4-Cl, 6-F isopropyl J1444 N NCH.sub.2 CCH 1-2 4-Cl, 6-F t-butyl J1445 N NCH.sub.2 CCH 1-2 4-Cl, 6-F CF.sub.3 J1446 N NCH.sub.2 CCH 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1447 N NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F CH.sub.3 J1448 N NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1449 N NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F isopropyl J1450 N NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F t-butyl J1451 N NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F CF.sub.3 J1452 N NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1453 N NCF.sub.3 1-2 4-Cl, 6-F CH.sub.3 J1454 N NCF.sub.3 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1455 N NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F isopropyl J1456 N NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F t-butyl J1457 N NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F CF.sub.3 J1458 N NCF.sub.3 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1459 NH N 2-3 4-Cl, 6-F CH.sub.3 J2460 NH N 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J2461 NH N 2-3 4-Cl, 6-F isopropyl J2462 NH N 2-3 4-Cl, 6-F t-butyl J2463 NH N 2-3 4-Cl, 6-F CF.sub.3 J2464 NH N 2-3 4-Cl, 6-F CF.sub.2 CF.sub.3 J2465 NH N 2-3 4-Cl, 6-F CH.sub.3 J3466 NH N 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J3467 NH N 2-3 4-Cl, 6-F isopropyl J3468 NH N 2-3 4-Cl, 6-F t-butyl J3469 NH N 2-3 4-Cl, 6-F CF.sub.3 J3470 NH N 2-3 4-Cl, 6-F CF.sub.2 CF.sub.3 J3471 NH N 2-3 4-Cl, 6-F CH.sub.3 J4472 NH N 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J4473 NH N 2-3 4-Cl, 6-F isopropyl J4474 NH N 2-3 4-Cl, 6-F t-butyl J4475 NH N 2-3 4-Cl, 6-F CF.sub.3 J4476 NH N 2-3 4-Cl, 6-F CF.sub.2 CF.sub.3 J4477 NH N 2-3 4-Cl, 6-F CH.sub.3 J5478 NH N 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J5479 NH N 2-3 4-Cl, 6-F isopropyl J5480 NH N 2-3 4-Cl, 6-F t-butyl J5481 NH N 2-3 4-Cl, 6-F CF.sub.3 J5482 NH N 2-3 4-Cl, 6-F CF.sub.2 CF.sub.3 J5483 NH NH 1-2 4-Cl, 6-F CH.sub.3 J1484 CH NH 1-2 4-Cl, 6-F n-C.sub.3 H.sub.7 J1485 CH NH 1-2 4-Cl, 6-F i-C.sub.3 H.sub.7 J1486 CH NH 1-2 4-Cl, 6-F t-C.sub.4 H.sub.9 J1487 CH NH 1-2 4-Cl, 6-F CH.sub.2 OH J1488 CH NH 1-2 4-Cl, 6-F CH.sub.2 CH.sub.2 OH J1489 CH NH 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OH J1490 CH NH 1-2 4-Cl, 6-F CONHCH.sub.3 J1491 CH NH 1-2 4-Cl, 6-F CON(CH.sub.3).sub.2 J1492 CH NH 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1493 CH NH 1-2 4-Cl, 6-F CO.sub.2 CH.sub.2 CH.sub.3 J1494 CH NH 1-2 4-Cl, 6-F Phenyl J1495 CH NH 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1496 CH NH 1-2 4-Cl, 6-F CH.sub.2 OCH.sub.3 J1497 CH NH 1-2 4-Cl, 6-F Benzyl J1498 CH NH 1-2 4-Cl, 6-F 4-chlorophenylmethyl J1499 CH NH 1-2 4-Cl, 6-F SO.sub.2 CH.sub.3 J1500 CH NH 1-2 4-Cl, 6-F CF.sub.3 J1501 CH NH 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OCOCH.sub.3 J1502 CH NH 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OH J1503 CH NH 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OCH.sub.3 J1504 CH NH 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1505 CH NH 1-2 4-Cl, 6-F CO.sub.2 Na J1506 CH NH 1-2 4-Cl, 6-F CONHSO.sub.2 CH.sub.3 J1507 CH NH 1-2 4-Cl, 6-F CHFCH.sub.3 J1508 CH NH 1-2 4-Cl, 6-F CH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3 J1509 CH NCH.sub.3 1-2 4-Cl, 6-F CH.sub.3 J1510 CH NCH.sub.3 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1511 CH NCH.sub.3 1-2 4-Cl, 6-F isopropyl J1512 CH NCH.sub.3 1-2 4-Cl, 6-F t-butyl J1513 CH NCH.sub.3 1-2 4-Cl, 6-F CF.sub.3 J1514 CH NCH.sub.3 1-2 4-Cl, 6-F CF.sub.2 CF.sub.3 J1515 CH NCH.sub.3 1-2 4-Cl, 6-F CHFCH.sub.3 J1516 CH NCH.sub.3 1-2 4-Cl, 6-F CON(CH.sub.3).sub.2 J1517 CH NCH.sub.3 1-2 4-Cl, 6-F CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 J1518 CH NCH.sub.3 1-2 4-Cl, 6-F CH.sub.2 CH.sub.2 CN J1519 CH NCH.sub.3 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OH J1520 CH NCH.sub.3 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OCOCH.sub.3 J1521 CH NCH.sub.3 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 NHSO.sub.2 CH.sub.3 J1522 CH NCH.sub.3 1-2 4-Cl, 6-F CO.sub.2 CH.sub.2 CH.sub.3 J1523 CH NC.sub.2 H.sub.5 1-2 4-Cl, 6-F CH.sub.3 J1524 CH NC.sub.2 H.sub.5 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1525 CH NC.sub.2 H.sub.5 1-2 4-Cl, 6-F isopropyl J1526 CH NC.sub.2 H.sub.5 1-2 4-Cl, 6-F t-butyl J1527 CH NC.sub.2 H.sub.5 1-2 4-Cl, 6-F CF.sub.3 J1528 CH NC.sub.2 H.sub.5 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1529 CH NC.sub.4 H.sub.9 1-2 4-Cl, 6-F CH.sub.3 J1530 CH NC.sub.4 H.sub.9 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1531 CH NC.sub.4 H.sub.9 1-2 4-Cl, 6-F isopropyl J1532 CH NC.sub.4 H.sub.9 1-2 4-Cl, 6-F t-butyl J1533 CH NC.sub.4 H.sub.9 1-2 4-Cl, 6-F CF.sub.3 J1534 CH NC.sub.4 H.sub.9 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1535 CH NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F CH.sub.3 J1536 CH NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1537 CH NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F isopropyl J1538 CH NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F t-butyl J1539 CH NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F CF.sub.3 J1540 CH NCH.sub.2 OCH.sub.3 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1541 CH NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CH.sub.3 J1542 CH NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1543 CH NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F isopropyl J 1544 CH NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F t-butyl J1545 CH NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CF.sub.3 J1546 CH NCO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1547 CH NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CH.sub.3 J1548 CH NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1549 CH NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F isopropyl J1550 CH NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F t-butyl J1551 CH NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CF.sub.3 J1552 CH NSO.sub.2 CH.sub.3 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1553 CH NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F CH.sub.3 J1554 CH NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1555 CH NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F isopropyl J1556 CH NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F t-butyl J1557 CH NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F CF.sub.3 J1558 CH NCH.sub.2 CHCH.sub.2 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1559 CH NCH.sub.2 C.tbd.CH 1-2 4-Cl, 6-F CH.sub.3 J1560 CH NCH.sub.2 C.tbd.CH 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1561 CH NCH.sub.2 C.tbd.CH 1-2 4-Cl, 6-F isopropyl J1562 CH NCH.sub.2 C.tbd.CH 1-2 4-Cl, 6-F t-butyl J1563 CH NCH.sub.2 C.tbd.CH 1-2 4-Cl, 6-F CF.sub.3 J1564 CH NCH.sub.2 C.tbd.CH 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1565 CH NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F CH.sub.3 J1566 CH NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1567 CH NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F isopropyl J1568 CH NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F t-butyl J1569 CH NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F CF.sub.3 J1570 CH NCH.sub.2 CO.sub.2 Me 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1571 CH NCH.sub.2 CHF.sub.2 1-2 4-Cl, 6-F CH.sub.3 J1572 CH NCH.sub.2 CHF.sub.2 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J1573 CH NCH.sub.2 CHF.sub.2 1-2 4-Cl, 6-F isopropyl J1574 CH NCH.sub.2 CHF.sub.2 1-2 4-Cl, 6-F t-butyl J1575 CH NCH.sub.2 CHF.sub.2 1-2 4-Cl, 6-F CF.sub.3 J1576 CH NCH.sub.2 CHF.sub.2 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J1577 CH NH 1-2 4-Cl, 6-F CH.sub.3 J2578 CH NH 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J2579 CH NH 1-2 4-Cl, 6-F isopropyl J2580 CH NH 1-2 4-Cl, 6-F t-butyl J2581 CH NH 1-2 4-Cl, 6-F CF.sub.3 J2582 CH NH 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J2583 CH NH 1-2 4-Cl, 6-F CH.sub.3 J3584 CH NH 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J3585 CH NH 1-2 4-Cl, 6-F isopropyl J3586 CH NH 1-2 4-Cl, 6-F t-butyl J3587 CH NH 1-2 4-Cl, 6-F CF.sub.3 J3588 CH NH 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J3589 CH NH 1-2 4-Cl, 6-F CH.sub.3 J4590 CH NH 1-2 4-Cl, 6-F C.sub.2 H.sub.5 J4591 CH NH 1-2 4-Cl, 6-F isopropyl J4592 CH NH 1-2 4-Cl, 6-F t-butyl J4593 CH NH 1-2 4-Cl, 6-F CF.sub.3 J4594 CH NH 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J4595 CH NH 1-2 4-Cl CO.sub.2 CH.sub.2 CH.sub.3 J5596 CH NH 1-2 4-Cl, 6-F CH.sub.3 J5597 CH NH 1-2 4-Cl, 6-F C.sub.2 H.sub.3 J5598 CH NH 1-2 4-Cl, 6-F isopropyl J5599 CH NH 1-2 4-Cl, 6-F t-butyl J5600 CH NH 1-2 4-Cl, 6-F CF.sub.3 J5601 CH NH 1-2 4-Cl, 6-F CO.sub.2 CH.sub.3 J5602 NH CH 2-3 4-Cl, 6-F CH.sub.3 J7603 NH CH 2-3 4-Cl, 6-F n-C.sub.3 H.sub.7 J1604 NH CH 2-3 4-Cl, 6-F i-C.sub.3 H.sub.7 J1605 NH CH 2-3 4-Cl, 6-F t-C.sub.4 H.sub.9 J1606 NH CH 2-3 4-Cl, 6-F CH.sub.2 OH J1607 NH CH 2-3 4-Cl, 6-F CH.sub.2 CH.sub.2 OH J1608 NH CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OH J1609 NH CH 2-3 4-Cl, 6-F CONHCH.sub.3 J1610 NH CH 2-3 4-Cl, 6-F CON(CH.sub.3).sub.2 J1611 NH CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J1612 NH CH 2-3 4-Cl, 6-F Phenyl J1613 NH CH 2-3 4-Cl, 6-F CF.sub.2 CF.sub.3 J1614 NH CH 2-3 4-Cl, 6-F CH.sub.2 OCH.sub.3 J1615 NH CH 2-3 4-Cl, 6-F Benzyl J1616 NH CH 2-3 4-Cl, 6-F 4-chlorophenylmethyl J1617 NH CH 2-3 4-Cl, 6-F SO.sub.2 CH.sub.3 J1618 NH CH 2-3 4-Cl, 6-F CF.sub.3 J1619 NH CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OCOCH.sub.3 J1620 NH CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OH J1621 NH CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 OCH.sub.3 J1622 NH CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J1623 NH CH 2-3 4-Cl, 6-F CO.sub.2 Na J1624 NH CH 2-3 4-Cl, 6-F CONHSO.sub.2 CH.sub.3 J1625 NH CH 2-3 4-Cl, 6-F CHFCH.sub.3 J1626 NH CH 2-3 4-Cl, 6-F CH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3 J1627 NH CH 2-3 4-Cl, 6-F CH.sub.3 J2628 NH CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J2629 NH CH 2-3 4-Cl, 6-F isopropyl J2630 NH CH 2-3 4-Cl, 6-F t-butyl J2631 NH CH 2-3 4-Cl, 6-F CF.sub.3 J2632 NH CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J2633 NH CH 2-3 4-Cl, 6-F CH.sub.3 J3634 NH CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J3635 NH CH 2-3 4-Cl, 6-F isopropyl J3636 NH CH 2-3 4-Cl, 6-F t-butyl J3637 NH CH 2-3 4-Cl, 6-F CF.sub.3 J3638 NH CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J3639 NH CH 2-3 4-Cl, 6-F CH.sub.3 J4640 NH CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J4641 NH CH 2-3 4-Cl, 6-F isopropyl J4642 NH CH 2-3 4-Cl, 6-F t-butyl J4643 NH CH 2-3 4-Cl, 6-F CF.sub.3 J4644 NH CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J4645 NH CH 2-3 4-Cl, 6-F CH.sub.3 J5646 NH CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J5647 NH CH 2-3 4-Cl, 6-F isopropyl J5648 NH CH 2-3 4-Cl, 6-F t-butyl J5649 NH CH 2-3 4-Cl, 6-F CF.sub.3 J5650 NH CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J5651 NH CCH.sub.3 2-3 4-Cl, 6-F CH.sub.3 J1652 NH CCH.sub.3 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J1653 NH CCH.sub.3 2-3 4-Cl, 6-F isopropyl J1654 NH CCH.sub.3 2-3 4-Cl, 6-F t-butyl J1655 NH CCH.sub.3 2-3 4-Cl, 6-F CF.sub.3 J1656 NH CCH.sub.3 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J1657 NH CCH.sub.2 CH.sub.3 2-3 4-Cl, 6-F CH.sub.3 J1658 NH CCH.sub.2 CH.sub.3 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J1659 NH CCH.sub.2 CH.sub.3 2-3 4-Cl, 6-F isopropyl J1660 NH CCH.sub.2 CH.sub.3 2-3 4-Cl, 6-F t-butyl J1661 NH CCH.sub.2 CH.sub.3 2-3 4-Cl, 6-F CF.sub.3 J1662 NH CCH.sub.2 CH.sub.3 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J1663 NH CCH.sub.2 CHF.sub.2 2-3 4-Cl, 6-F CH.sub.3 J1664 NH CCH.sub.2 CHF.sub.2 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J1665 NH CCH.sub.2 CHF.sub.2 2-3 4-Cl, 6-F isopropyl J1666 NH CCH.sub.2 CHF.sub.2 2-3 4-Cl, 6-F t-butyl J1667 NH CCH.sub.2 CHF.sub.2 2-3 4-Cl, 6-F CF.sub.3 J1668 NH CCH.sub.2 CHF.sub.2 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J1669 NH CH 2-3 4-Cl, 6-F CH.sub.3 J2670 NH CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J2671 NH CH 2-3 4-Cl, 6-F isopropyl J2672 NH CH 2-3 4-Cl, 6-F t-butyl J2673 NH CH 2-3 4-Cl, 6-F CF.sub.3 J2674 NH CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J2675 NH CH 2-3 4-Cl, 6-F CH.sub.3 J3676 NH CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J3677 NH CH 2-3 4-Cl, 6-F isopropyl J3678 NH CH 2-3 4-Cl, 6-F t-butyl J3679 NH CH 2-3 4-Cl, 6-F CF.sub.3 J3680 NH CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J3681 NH CH 2-3 4-Cl, 6-F CH.sub.3 J4682 NH CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J4683 NH CH 2-3 4-Cl, 6-F isopropyl J4684 NH CH 2-3 4-Cl, 6-F t-butyl J4685 NH CH 2-3 4-Cl, 6-F CF.sub.3 J4686 NH CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J4687 NH CH 2-3 4-Cl, 6-F CH.sub.3 J5688 NH CH 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J5689 NH CH 2-3 4-Cl, 6-F isopropyl J5690 NH CH 2-3 4-Cl, 6-F t-butyl J5691 NH CH 2-3 4-Cl, 6-F CF.sub.3 J5692 NH CH 2-3 4-Cl, 6-F CO.sub.2 CH.sub.3 J5693 NCH.sub.3 CH 2-3 4-Cl, 6-F CF.sub.3 J1694 NH CH 2-3 4-Cl CF.sub.3 J1695 CH NH 1-2 4-Cl, 6-F CF.sub.3 J1696 CH NCH.sub.2 C.sub.6 H.sub.5 1-2 4-Cl, 6-F CF.sub.3 J1697 CH NCH.sub.2 CO.sub.2 C.sub.2 H.sub.5 1-2 4-Cl, 6-F CF.sub.3 J1698 CH NCOCH.sub.3 1-2 4-Cl, 6-F CF.sub.3 J1699 CH NCH.sub.2 C.tbd.N 1-2 4-Cl, 6-F CF.sub.3 J1700 CH NH 1-2 4-Cl, 6-F CF.sub.3 J1701 CH NH 1-2 4-Cl, 6-F CO.sub.2 C.sub.2 H.sub.5 J1702 CH NH 1-2 4-Cl CO.sub.2 C.sub.2 H.sub.5 J1703 N O 1-2 4-Cl, 6-F CH.sub.3 J7704 O CH 1-2 4-Cl, 6-F C(CH.sub.3).sub.2 OH J7705 NH N 2-3 4-Cl, 6-F CF.sub.3 J6706 NH N 2-3 4-Cl, 6-F C(CH.sub.3).sub.3 J6707 NH N 2-3 4-Cl, 6-F CF.sub.3 J7708 NH N 2-3 4-Cl, 6-F CH.sub.2 C(CH.sub.3).sub.3 J1709 NH N 2-3 4-Cl, 6-F 3,5-dimethylisoxazolyl J1710 NH N 2-3 4-Cl, 6-F pyridin-2-yl J1711 NCOCH.sub.3 N 2-3 4-Cl, 6-F H J1712 NH N 2-3 4-Cl, 6-F C.sub.7 F.sub.15 J1713 NH N 2-3 4-Cl, 6-F CHCl.sub.2 J1714 NH N 2-3 4-Cl, 6-F NHCO.sub.2 C.sub.2 H.sub.5 J1715 NH N 2-3 4-Cl, 6-F CH(CH.sub.3)NHCH.sub.2 CO.sub.2 C.sub.2 H.sub.5 J1716 NH N 2-3 4-Cl, 6-F CH(CH.sub.3)OCOCH.sub.3 J1717 NH N 2-3 4-Cl, 6-F C(CH.sub.3).dbd.CH.sub.2 J1718 NH N 2-3 4-Cl, 6-F CH.dbd.C(CH.sub.3).sub.2 J1719 NH N 2-3 4-Cl, 6-F CH(Br)CH.sub.3 J1720 NH N 2-3 6-F CF.sub.3 J1721 NH N 2-3 4-Cl, 6-F CH.dbd.NC.sub.6 H.sub.5 J1722 NH N 2-3 4-Cl, 6-F CH.sub.2 OCOCH.sub.3 J1723 NH N 2-3 4-Cl, 6-F CH(OCH.sub.3)C.sub.6 H.sub.5 J1724 NH N 2-3 4-Cl, 6-F CH(OCOCH.sub.3)C.sub.6 H.sub.5 J1725 NH N 2-3 4-Cl, 6-F SCH.sub.3 J1726 NH N 2-3 4-Cl, 6-F C.sub.2 H.sub.5 J5727 NCH.sub.3 N 2-3 4,6-Cl.sub.2 CF.sub.3 J1728 N NCH.sub.3 2-3 4,6-Cl.sub.2 CF.sub.3 J1729 NH NH -- 4-Cl, 6-F CF.sub.3 J1730 NH N 2-3 4,6-Cl.sub.2 CF.sub.3 J5731 NH N 2-3 4-Cl, 6-F SO.sub.2 CH.sub.3 J1732 NH N 2-3 4-Br, 6-F CF.sub.3 J1733 NH N 2-3 4-Br, 6-F C.sub.2 H.sub.5 J1734 NH N 2-3 4-Cl, 6-F CH.sub.2 OH J1735 NH N 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 OH J1736 NH N 2-3 4-Cl, 6-F C(CH.sub.3)OCH.sub.2 C.sub.6 H.sub.5 J1737 NH N 2-3 4-Cl, 6-F SH J1738 NH N 2-3 4-Cl, 6-F SCH(CH.sub.3)C.tbd.N J1739 NH N 2-3 4-Cl, 6-F SC.sub.2 H.sub.5 J1740 NH N 2-3 4-Cl, 6-F SCH.sub.2 C.tbd.CH J1741 NH N 2-3 4-Cl, 6-F SCH.sub.2 C.sub.6 H.sub.5 J1742 NH N 2-3 4-Cl, 6-F SC.tbd.N J1743 NH N 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 CH.sub.2 SC.tbd.N J1744 NH N 2-3 4-Cl, 6-F SCH(CH.sub.3)CO.sub.2 C.sub.2 H.sub.5 J1745 NH N 2-3 4-Cl, 6-F SCH(CH.sub.3)CON(CH.sub.3).sub.2 J1746 NH N 2-3 4-Cl, 6-F SCH.sub.2 C.tbd.CH J5747 NH N 2-3 4-Cl, 6-F SCH.sub.2 C.dbd.CH.sub.2 J1748 NH N 2-3 4-Cl, 6-F SCH.sub.2 C.tbd.N J1749 NH N 2-3 4-Cl, 6-F SCH.sub.2 C.tbd.CCH.sub.2 Cl J1750 O CH 2-3 4-Cl, 6-F CH.sub.2 OCONHCH.sub.3 J1751 O CH 2-3 4-Cl, 6-F CH.sub.2 NHCOCH.sub.2 (C.sub.6 H.sub.4, J1 2-NO.sub.2) J1752 O CH 2-3 4-Cl, 6-F C(CH.sub.3)(OH)C.sub.6 H.sub.5 J1753 O CH 2-3 4-Cl, 6-F CH.sub.2 NH.sub.2 J1754 O CH 2-3 4-Cl, 6-F C(CH.sub.3)(OH)CH(CH.sub.3).sub.2 J1755 O CH 2-3 4-Cl, 6-F CH.sub.2 NHCOCH.sub.3 J1756 O CH 2-3 4-Cl, 6-F CH.sub.2 NHSO.sub.2 CH.sub.3 J1757 O CH 2-3 4-Cl, 6-F C(CH.sub.3).sub.2 F J1758 O CH 2-3 4-Cl, 6-F CH.sub.2 CO.sub.2 H J1759 O CH 2-3 4-Cl, 6-F CH.sub.2 CON(CH.sub.3).sub.2 J1760 O CH 2-3 4-Cl, 6-F CH.sub.2 CON(CH.sub.3)(OCH.sub.3) J1761 O CH 2-3 4-Cl, 6-F CH.sub.2 CONHCH.sub.3 J1762 O CH 2-3 4-Cl, 6-F CH.sub.2 CONH.sub.2 J1763 O CH 2-3 4-Cl, 6-F C.sub.2 H.sub.4 CON(CH.sub.3)(OCH.sub.3) J1764 O CH 2-3 4-Cl, 6-F C.sub.2 H.sub.4 CO.sub.2 CH.sub.3 J1765 O CH 2-3 4-Cl, 6-F C.sub.3 H.sub.6 OH J1766 O CH 2-3 4-Cl, 6-F C.sub.2 H.sub.4 CONHCH.sub.3 J1767 NH N 2-3 4-Cl SCF.sub.3 J1768 NH N 2-3 4-Cl CF.sub.3 J1769 NH N 2-3 4-Cl CF.sub.3 J3__________________________________________________________________________
TABLE 3__________________________________________________________________________Characterizing DataMelting Points or Physical States of Representative CompoundsNo. MP/State No. MP/State No. MP/State No. MP/State__________________________________________________________________________ 1 OIL 246 45-9 377 122-30 722 117-122 RESIN 16 70-72 247 35-8 378 200 C> 723 107-112 RESIN 25 OIL 248 67-71 379 116-22 724 108-114 RESIN 26 OIL 249 84-9 380 201-4 725 135-140 RESIN 28 OIL 250 65-68 381 117-24 726 >210 30 OIL 251 55-7 382 193-5 727 182-183 38 246-9 252 OIL 383 131-40 728 174-175 42 >250 253 GLASS 384 103-5 729 >205 43 SOLID 254 71-5 385 158-160 730 >205 49 OIL 255 134-8 386 132-5 731 150-152 RESIN 96 OIL 256 145-7 387 112-4 732 195-200 98 >245 257 OIL 388 107-9 733 >205 99 OIL 258 232-40 399 177.5-8.5 734 SOLID100 OIL 259 165-9 405 130 735 118-121 RESIN101 OIL 260 55-8 469 98-100 736 88-92102 OIL 261 65-7 481 SOLID 737 >200103 OIL 262 75-7 493 187-8 738 133-135104 OIL 263 >50 500 208-10 739 130-132105 >250 264 155-7 513 178-181 740 178-180106 OIL 265 130-6 522 78-80 741 118-121 RESIN107 OIL 266 258-61 527 152-154 742 150-155108 >250 267 110-8 563 165-166 743 SOLID109 OIL 268 73-7 595 >240 744 160-162110 OIL 269 270-5 618 235-237.5 745 >200112 86-88 270 265-72 693 60-65 746 106-109221 193.5-6 271 62-72 694 221.5-223 747 98-100222 183-6 272 OIL 695 160-162 748 104-110 RESIN223 OIL 273 220-2.5 696 173-177 749 155-158 RESIN224 OIL 274 116 SOFTENS 697 60-63 750 137-139225 OIL 275 OIL 698 142-145.5 751 189-190226 63-6 276 145-53 699 95-102 752 78-82227 134-6 277 179-82 700 160-162 753 87-89228 42-5 278 189-92 701 245-248 754 75-77229 OIL 279 197-8 702 258-260 755 96-98230 163-5 280 215-6 705 102-103 756 90-92231 65-70 362 152-8 706 88-89 757 60-62232 186-91 363 >165 708 140 DEC 758 95-97233 85-90 364 SOLID 709 >200 759 144-146234 65-70 365 172-7 710 130 RESIN 760 146-147235 63-7 366 130 711 >200 761 70-76236 56-8 367 150-5 712 93-98 RESIN 762 185-187237 141-2 368 87-93 713 123-130 RESIN 763 63-65238 143-5 369 125-30 714 160-165 RESIN 754 OIL239 162-4 370 130 715 90-95 765 50-54240 72-6 371 SOLID 716 115-120 RESIN 766 172-173241 67-70 372 SOLID 717 120-125 767 239-241242 163-5 373 160 718 110-116243 51-55 374 190 719 120-125244 OIL 375 >200 720 128-132 RESIN245 OIL 376 142-8 721 145-150__________________________________________________________________________
Biological Testing
The benzofused heterocyclic compounds of this invention were tested for pre- and postemergence herbicidal activity using a variety of crops and weeds. The test plants included soybean (Glycine max var. Winchester), field corn (Zea mays var. Pioneer 3732), wheat (Triticum aestivum var. Lew), morningglory (Ipomea lacunosa or Ipomea hederacea), velvetleaf (Abutilon theophrasti), green foxtail (Setaria viridis), Johnsongrass (Sorghum halepense), blackgrass (Aloepecurus myosuroides), common chickweed (Stellaria media), and common cocklebur (Xanthium strumarium L.).
For preemergence testing, two disposable fiber flats (8 cm.times.15 cm.times.25 cm) for each rate of application of each candidate herbicide were filled to an approximate depth of 6.5 cm with steam-sterilized sandy loam soil. The soil was leveled and impressed with a template to provide five evenly spaced furrows 13 cm long and 0.5 cm deep in each flat. Seeds of soybean, wheat, corn, green foxtail, and johnsongrass were planted in the furrows of the first flat, and seeds of velvetleaf, morningglory, common chickweed, cocklebur, and blackgrass were planted in the furrows of the second flat. The five-row template was employed to firmly press the seeds into place. A topping soil of equal portions of sand and sandy loam soil was placed uniformly on top of each flat to a depth of approximately 0.5 cm. Flats for postemergence testing were prepared in the same manner except that they were planted 9-14 days prior to the preemergence flats and were placed in a greenhouse and watered, thus allowing the seeds to germinate and the foliage to develop.
In both pre- and postemergence tests, a stock solution of the candidate herbicide was prepared by dissolving 0.27 g of the compound in 20 mL of water/acetone (50/50) containing 0.5% v/v sorbitan monolaurate. For an application rate of 3000 g/ha of herbicide a 10 mL portion of the stock solution was diluted with water/acetone (50/50) to 45 mL. The volumes of stock solution and diluent used to prepare solutions for lower application rates are shown in the following table:
______________________________________Application Volume of Volume of Total, VolumeRate Stock Solution Acetone/Water of Spray Solution(g/ha) (mL) (mL) (mL)______________________________________3000 10 35 451000 3 42 45 300 1 44 45 100 0.3 45 45.3 30 0.1 45 45.1 10 0.03 45 45.03 3 0.01 45 45.01______________________________________
The preemergence flats were initially subjected to a light water spray. The four flats were placed two by two along a conveyor belt (i.e., the two preemergence followed by the two postemergence flats). The conveyor belt fed under a spray nozzle mounted about ten inches above the postemergent foliage. The preemergent flats were elevated on the belt so that the soil surface was at the same level below the spray nozzle as the foliage canopy of the postemergent plants. The spray of herbicidal solution was commenced and once stabilized, the flats were passed under the spray at a speed to receive a coverage equivalent of 1000 L/ha. At this coverage the application rates are those shown in the above table for the individual herbicidal solutions. The preemergence flats were watered immediately thereafter, placed in the greenhouse and watered regularly at the soil surface. The postemergence flats were immediately placed in the green-house and not watered until 24 hours after treatment with the test solution. Thereafter they were regularly watered at ground level. After 12-17 days the plants were examined and the phytotoxicity data were recorded.
Herbicidal activity data at selected application rates are given for various compounds of this invention in Table 4 and Table 5. The test compounds are identified by numbers which correspond to those in Tables 1 and 2.
Phytotoxicity data were taken as percent control. Percent control was 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, Ala., 1977. The rating system is as follows:
______________________________________Herbicide Rating SystemRating DescriptionPercent of Main Crop WeedControl Categories Description Description______________________________________ 0 No effect No crop No weed reduction/injury control10 Slight dis- Very poor weed coloration or stunting control20 Slight Some discoloration, Poor weed eftect stunting or control stand loss30 Crop injury Poor to defi- more pronounced cient weed but not lasting control40 Moderate injury, Deficient weed crop usually recovers control50 Moderate Crop injury Deficient to effect more lasting, moderate weed recovery doubtful control60 Lasting crop Moderate weed injury, no recovery control70 Heavy injury and Control some- stand loss what less than satisfactory80 Severe Crop nearly destroyed Satisfactory to a few survivors weed control90 Only occasional Very good to live plants left excellent control100 Complete Complete crop Complete weed effect destruction destruction______________________________________
Formulation
The compounds of the present invention were tested in the laboratory as water/acetone (50/50) solutions containing 0.5% v/v sorbitan monolaurate emulsifier. It is expected that all formulations normally employed in applications of herbicides would be usable with the compounds of the present invention. These include wettable powders, emulsifiable concentrates, water suspensions, flowable concentrates, and the like.
TABLE 4__________________________________________________________________________PREEMERGENCE HERBICIDAL ACTIVITY (% CONTROL)No. SOY WHT CRN ABUTH IPOSS STEME XANPE ALOMY SETVI SORHA__________________________________________________________________________ 1 100 85 90 100 100 100 100 90 100 95 16 100 70 90 100 100 100 90 80 100 95 25 100 100 100 100 100 100 95 90 100 100 26 100 90 90 100 100 100 100 95 100 100 28 100 100 95 100 100 100 100 100 100 100 30 100 100 95 100 100 100 90 100 100 100 38 60 50 80 100 100 0 70 30 75 60 42 0 10 0 100 60 30 20 50 30 0 43 50 40 80 100 100 10 -- 60 70 80 49 95 50 80 100 100 20 90 -- 100 90 96 100 90 95 100 100 100 -- 90 100 95 98 50 40 80 80 75 70 60 10 30 65 99 40 50 60 100 100 100 -- 60 100 65100 40 30 80 100 100 20 -- 60 50 70101 80 70 100 100 100 -- 80 80 100 100102 20 30 10 100 70 -- 50 90 100 60103 50 50 80 100 100 -- 70 90 100 70104 100 100 100 100 100 -- 100 100 100 100106 30 40 70 100 100 95 60 70 90 55107 80 60 90 100 100 100 40 75 100 100108 0 0 10 70 50 40 10 50 50 30109 100 100 90 100 100 100 100 100 100 100110 100 50 70 100 90 100 40 80 100 100112 100 100 100 100 100 100 100 100 100 100221 70 60 85 100 100 80 ND ND 100 95222 100 70 90 100 100 100 100 ND 100 100223 100 50 80 100 100 100 90 ND 100 100224 100 80 90 100 100 100 95 80 100 100225 40 20 30 90 50 70 50 ND 100 60226 70 50 70 100 90 90 60 ND 100 80227 100 80 90 100 100 100 ND 95 100 100228 100 80 95 100 100 100 90 ND 100 100229 100 70 90 100 100 100 95 80 100 100230 100 40 80 100 100 100 100 80 100 100231 100 80 100 100 100 100 100 90 100 100232 20 30 50 90 80 20 10 ND 40 25233 40 30 70 100 95 20 20 ND 60 50234 100 100 100 100 100 100 100 80 100 100235 100 90 100 100 100 100 100 80 100 100236 100 70 95 100 100 100 100 80 100 100237 100 90 90 100 100 100 100 100 100 100238 100 60 70 100 100 60 80 50 90 90239 100 70 90 100 100 100 ND ND 100 90240 100 95 95 100 100 100 100 ND 100 100241 60 70 95 100 100 100 100 ND 100 100242 100 100 100 100 100 100 100 100 100 100243 100 80 95 100 100 100 100 ND 100 100244 95 80 100 100 90 70 100 70 100 100245 100 60 80 100 100 90 100 70 100 80246 100 100 100 100 100 100 100 100 100 100247 100 90 90 100 100 95 100 85 100 100248 100 90 95 100 100 100 100 95 100 100249 100 80 95 100 100 100 90 80 10 100250 80 40 50 100 100 ND 100 60 100 70251 90 90 95 100 100 95 100 90 100 100252 100 100 100 100 100 100 ND 100 100 100253 100 95 100 100 100 100 ND ND 100 100254 25 20 80 100 50 30 50 60 100 80255 100 90 95 100 100 100 100 ND 100 100256 100 80 95 100 100 100 ND 70 100 90257 40 0 10 90 70 0 20 20 70 10258 30 30 75 100 60 0 60 ND 40 40259 70 40 80 100 70 100 55 ND 100 95260 100 70 80 100 100 100 100 95 100 100261 100 80 95 100 100 100 90 80 100 100262 90 40 40 100 100 100 100 50 100 70263 100 50 65 100 100 100 95 75 100 70264 0 0 10 20 0 20 30 0 10 10265 70 40 80 90 100 20 70 ND 80 60266 50 30 60 40 70 0 0 ND 30 30267 0 10 20 10 10 0 50 50 5 0268 30 30 50 100 95 20 0 ND 60 60269 60 30 80 100 100 100 100 70 100 75270 70 70 90 100 100 ND 60 65 100 100271 80 70 90 100 100 100 100 80 100 90272 20 0 20 100 70 100 20 70 90 60273 100 80 90 100 100 100 100 90 100 100274 100 100 90 100 100 90 100 95 100 100275 100 80 100 100 100 100 100 80 100 95362 100 100 100 100 100 100 100 100 100 100363 100 100 100 100 100 100 100 100 100 100364 100 60 80 100 100 100 100 80 100 80365 ND 30 30 100 100 100 100 60 75 60366 10 10 0 70 20 0 10 0 50 40367 100 95 100 100 100 100 100 90 100 100368 100 100 95 100 100 100 100 95 100 100369 100 100 100 100 100 100 100 100 100 100370 100 100 95 100 100 100 100 90 100 100371 100 95 100 100 100 100 100 100 100 100372 100 90 95 100 100 100 100 80 100 80373 100 70 90 100 100 100 100 70 100 90374 30 0 10 100 95 90 80 40 100 75375 80 30 90 100 80 95 80 80 100 95376 50 60 80 100 100 100 100 100 100 70377 100 70 90 100 100 ND 100 100 100 100378 90 70 90 100 100 100 100 80 100 95379 100 50 70 100 100 ND 100 80 100 95380 80 35 20 100 100 ND 80 90 100 70381 100 40 80 100 100 ND 100 90 100 80382 60 45 30 100 70 ND 60 90 95 80383 80 40 20 100 60 ND 70 80 75 55399 95 80 95 100 95 100 70 60 100 0493 80 70 90 100 100 100 70 75 100 100500 95 75 90 100 100 100 100 75 100 100522 90 40 80 100 100 100 50 75 100 100595 10 0 0 60 50 10 20 ND 0 40__________________________________________________________________________ Rate of Application is 0.3 Kg/Ha. SOY is soybean; WHT is wheat; CRN is corn; ABUTH is velvetleaf; IPOSS is morningglory; STEME is chickweed; XANPE is cocklebur; ALOMY is blackgrass, SETVI is green foxtail; SORHA is johnsongrass
TABLE 5__________________________________________________________________________POSTEMERGENCE HERBICIDAL ACTIVITY (% CONTROL)No. SOY WHT CRN ABUTH IPOSS STEME XANPE ALOMY SETVI SORHA__________________________________________________________________________ 1 95 65 80 100 100 90 100 70 80 80 16 95 60 80 100 100 70 95 70 80 80 25 100 80 90 100 100 100 100 80 100 90 26 96 60 80 100 100 80 100 80 100 80 28 100 80 80 100 100 100 90 100 100 95 30 95 80 90 100 100 100 100 90 100 100 38 70 35 60 100 100 0 45 20 40 50 42 65 30 60 90 60 -- 50 40 100 20 43 80 30 70 100 100 70 50 -- 50 50 49 95 70 80 100 100 40 30 -- 100 90 96 100 90 90 100 100 100 100 -- 100 100 98 40 10 50 60 20 5 20 5 40 20 99 80 40 80 100 100 95 70 -- 70 65100 85 40 60 90 100 50 50 -- 30 40101 95 50 80 100 100 -- -- 60 65 65102 80 30 75 100 100 -- -- 60 90 60103 90 50 80 100 80 -- 80 70 100 60104 100 100 100 100 100 -- -- -- 100 100106 80 30 75 100 100 -- -- 60 100 70107 95 40 100 100 100 100 -- 90 100 100108 50 20 60 20 60 0 10 10 70 20109 90 90 80 100 100 -- 100 90 100 90110 80 40 50 100 100 100 70 80 70112 100 100 100 100 100 100 100 100 100 100221 95 50 60 100 100 100 60 40 70 70222 100 70 90 100 100 100 100 100 100 100223 95 40 90 100 100 100 100 ND 100 100224 95 70 100 100 100 100 100 90 100 ND225 60 30 60 100 75 ND 70 ND 90 60226 70 40 80 100 95 80 90 ND 100 80227 95 60 90 100 100 100 100 100 100 100228 90 50 80 100 100 80 95 ND 100 90229 95 60 80 100 100 100 100 70 100 100230 95 40 80 100 100 90 100 70 100 90231 100 70 100 100 100 100 ND 100 100 100232 75 50 30 100 80 20 40 ND 30 10233 90 30 60 100 100 30 30 ND 30 30234 100 100 100 100 100 100 100 100 100 100235 100 100 100 100 100 100 100 100 100 100236 100 75 90 100 100 100 100 80 100 100237 100 95 100 100 100 ND 100 100 100 100238 80 30 70 100 100 ND 100 40 80 70239 95 60 80 100 100 100 100 ND 100 80240 95 95 100 100 100 100 100 ND 100 100241 90 60 70 100 100 85 95 ND 100 70242 100 100 100 100 100 100 100 100 100 100243 95 70 95 100 100 100 100 ND 100 100244 95 60 90 100 100 100 100 75 100 ND245 85 40 75 100 100 60 70 50 70 70246 95 100 100 100 100 100 100 ND 100 100247 95 80 100 100 100 100 100 100 100 ND248 80 50 95 100 100 100 100 ND 100 100249 95 80 100 100 100 100 100 100 100 ND250 95 50 80 100 100 80 100 40 100 100251 95 70 90 100 100 100 95 100 100 95252 95 90 100 100 100 100 ND 100 100 100253 95 100 100 100 100 100 100 ND 100 100254 95 40 80 100 70 ND 95 50 100 80255 100 100 100 100 100 100 100 ND 100 100256 100 80 90 100 100 100 100 80 100 100257 70 20 70 100 60 30 70 30 70 50258 80 30 60 80 70 5 50 30 60 50259 80 35 75 100 90 30 70 55 80 70260 90 80 70 100 100 ND 100 90 100 90261 95 80 100 100 100 100 100 100 100 100262 95 60 80 100 100 95 95 50 100 80263 95 80 90 100 100 100 100 60 90 70264 50 20 50 40 40 0 30 0 ND 20265 70 40 60 100 100 30 20 ND 40 20266 60 40 60 50 60 10 10 ND 40 40267 50 15 50 80 40 10 10 20 30 20268 70 40 60 50 90 20 ND ND 70 40269 90 40 70 100 80 80 ND ND 70 60270 70 40 50 100 60 40 ND 50 50 50271 80 40 60 100 100 100 ND ND 70 50272 50 30 45 100 60 50 50 20 70 40273 95 60 95 100 100 90 100 80 100 100274 95 60 95 100 100 90 100 90 100 100275 100 70 90 100 100 100 100 95 100 100362 100 100 100 100 100 100 ND 100 100 100363 100 100 100 100 100 ND 100 100 100 100364 95 40 80 100 100 100 100 ND 100 100365 100 40 70 100 100 100 ND 70 80 30366 70 30 80 95 80 30 100 30 50 50367 100 100 100 100 100 100 100 100 100 100368 100 100 100 100 100 100 100 100 100 100369 100 80 100 100 100 ND 100 100 100 100370 100 95 100 100 100 100 100 100 100 100371 95 100 100 100 100 100 100 ND 100 100372 100 100 100 100 100 100 100 100 100 100373 100 80 100 100 100 100 100 100 100 100374 80 25 30 100 95 80 100 25 80 60375 95 40 90 100 95 100 100 90 80 100376 90 50 95 100 100 ND 100 90 100 100377 95 80 100 100 100 ND 100 100 100 100378 90 40 90 100 90 ND 100 80 100 100379 95 80 100 100 100 ND 100 70 100 100380 95 30 95 100 100 ND 100 70 100 80381 95 40 95 100 100 ND 100 100 100 100382 80 40 100 100 100 ND 100 80 90 80383 95 40 95 100 95 ND 100 60 95 70399 95 30 70 100 100 100 100 50 70 60493 95 60 90 100 100 80 100 65 100 100500 95 65 95 100 100 90 100 80 100 100522 90 45 90 100 100 100 100 50 100 100595 50 10 60 30 40 0 20 10 20 20__________________________________________________________________________ Rate of Application is 0.3 Kg/Ha. SOY is soybean; WHT is wheat; CRN is corn; ABUTH is velvetleaf; IPOSS is morningglory; STEME is chickweed; XANPE is cocklebur; ALOMY is blackgrass, SETVI is green foxtail; SORHA is johnsongrass
Herbicidal compositions are prepared by combining herbicidally effective amounts of the active compounds 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. It is to be understood that the amounts specified in this specification are intended to be approximate only, as if the word -about" were placed in front of the amounts specified.
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 post-emergence 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 80.0 parts of the herbicidal compound, 17.9 parts of Palmetto clay, and 1.0 part of sodium lignosulfonate and 0.3 part of sulfonated aliphatic polyester as wetting agents. Additional wetting agent and/or oil will frequently be added to the tank mix for post-emergence 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 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, isphorone, or other non-volatile organic solvents. 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.
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 will typically contain active ingredients 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.
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 surface-active agents are available in commerce. Surface-active agents, when used, normally comprise 1 to 15% by weight of the composition.
Other useful formulations include suspensions of the active ingredient in a relatively non-volatile solvent such as water, corn oil, kerosene, propylene glycol, or other suitable solvents.
Still 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 relative 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 free-flowing, non-dusty, and readily water-soluble or water-miscible. The soluble or dispersible granular formulations described in U.S. Pat. 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, e.g. 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 (e.g., four times the rates mentioned above) may be employed.
The active herbicidal compounds of the present invention may also be used in combination with other herbicides. Such herbicides include, for example: N-(phosphonomethyl) glycine (--glyphosate"); aryloxyalkanoic acids such as (2,4-dichlorophenoxy)acetic acid (-2,4-D"), (4-chloro-2-methylphenoxy)acetic acid (--MCPA"), (+/-)-2-(4-chloro-2-methylphenoxy)propanoic acid (MCPP); ureas such as N,N-dimethyl-N'-[4-(1-methylethyl)phenyl]urea (-isoproturon"); imidazolinones such as 2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-pyridinecarboxylic acid (-imazapyr"), a reaction product comprising (+/-)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-4-methylbenzoic acid and (+/-)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-5-methylbenzoic acid (-imazamethabenz"), (+/-)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-5-ethyl-3-pyridinecarboxylic acid (-imazethapyr"), and (+/-)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-quinolinecarboxylic acid (-imazaquin"); diphenyl ethers such as 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid (-acifluorfen"), methyl 5-(2,4-dichlorophenoxy)-2-nitrobenzoate (-bifenox"), and 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide (-fomasafen"); hydroxy-benzonitriles such as 4-hydroxy-3,5-diiodobenzonitrile (-ioxynil") and 3,5-dibromo-4-hydroxybenzonitrile (-bromoxynil"); sulfonylureas such as 2-[[[[(4-chloro-6-methoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]benzoic acid (-chlorimuron"), 2-chloro-N-[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]benzenesulfonamide (-chlorsulfuron") , 2-[[[[[(4,6- dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]methyl]benzoic acid (-bensulfuron"), 2-[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]-1-methyl-1H-pyrazol-4-carboxylic acid (-pyrazosulfuron"), 3-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-2-thiophenecarboxylic acid (-thifensulfuron"), and 2-(2-chloroethoxy)-N-[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]benzenesulfonamide (-triasulfuron"); 2-(4-aryloxyphenoxy)alkanoic acids such as (+/-)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]phenoxy]propanoic acid (-fenoxaprop"), (+/-)-2-[4-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenoxy]propanoic acid (-fluazifop"), (+/-)-2-[4-(6-chloro-2-quinoxalinyl)oxy]phenoxy]propanoic acid (-quizalofop"), and (+/-)-2-[-(2,4-dichlorophenoxy)phenoxy]propanoic acid (-diclofop"); benzothiadiazinones such as 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one 2,2-dioxide (-bentazone"); 2-chloroacetanilides such as N-butoxymethyl)-2-chloro-2', 6'-diethylacetanilide (-butachlor"); 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetamide (-metachlor"), 2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl)acetamide (-acetochlor"), and (RS)-2-chloro-N-(ethoxymethyl)-N-(2-methoxy-1-methylethyl)acetamide (-dimethenamide"); arenecarboxylic acids such as 3,6-dichloro-2-methoxybenzoic acid (-dicamba"); and pyridyloxyacetic acids such as [(4-amino-3,5-dichloro-6-fluoro-2-pyridinyl)oxy]acetic acid (-fluroxypyr").
It is apparent that various modifications may be made in the formulations and application of the compounds of the present invention without departing from the inventive concepts herein, as defined in the claims.

Number	Name	Date
3920442	Albert et al.	Nov 1975
5354730	Enomoto et al.	Oct 1994
5661108	Crawford et al.	Aug 1997
5753595	Crawford et al.	May 1998

Number	Date	Country
0 255 047 A1	Mar 1988	EPX
0 304 920 A2	Mar 1989	EPX
0 373 461 A2	Jun 1990	EPX
0 476 697 A1	Mar 1992	EPX
0 561 319 A1	Sep 1993	EPX
0 617 033 A1	Sep 1994	EPX
195 04 188 A1	Aug 1996	DEX
195 23 640 A1	Jan 1997	DEX
WO 9505079	Feb 1995	WOX
WO 9708170	Mar 1997	WOX
WO 9729105	Aug 1997	WOX
WO 9742188	Nov 1997	WOX

Cycloimido-substituted benzofused heterocyclic herbicides

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