Substituted pyrimidine and pyridine herbicides

This application was filed under 35 U.S.C. 371 from International Application PCT/US98/22088 filed Oct. 20, 1998 which claims priority benefit from Provisional Application No. 60/067,418 filed Dec. 3, 1997 and Provisional Application No. 60/068,432 filed Dec. 22, 1997.

This invention relates to certain pyrimidines and pyridines, their N-oxides, agriculturally suitable salts, compositions thereof, and methods of their use for controlling undesirable vegetation.

The control of undesired vegetation is extremely important in achieving high crop efficiency. Achievement of selective control of the growth of weeds especially in such useful crops as rice, soybean, sugar beet, corn (maize), potato, wheat, barley, tomato and plantation crops, among others, is very desirable. Unchecked weed growth in such useful crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of undesired vegetation in noncrop areas is also important. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action.

EP 723,960 discloses herbicidal substituted pyrimidines and pyridines of Formula i:

wherein, inter alia,

A is an optionally substituted aryl or 5- or 6-membered nitrogen containing heteroaromatic group;

X is oxygen or sulfur;

Z is nitrogen or CH;

R 1 and R 2 are independently hydrogen, halogen, alkyl, haloalkyl, nitro or cyano;

n is 0, 1 or 2; and

m is 0 to 5.

The pyrimidines and pyridines of the present invention are not disclosed in this reference.

This invention is directed to compounds of Formula I including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, as well as agricultural compositions containing them and a method of their use for controlling undesirable vegetation:

W is N or CR 11 ;

X, Y and Z are independently N or CR 12 ;

R 1 and R 2 are independently H, halogen, cyano, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 2 -C 4 alkoxyalkyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkoxyalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 4 alkenyloxy, C 3 -C 4 alkynyloxy, S(O) n R 13 , C 2 -C 4 alkylthioalkyl, C 2 -C 4 alkylsulfonylalkyl, C 1 -C 4 alkylamino or C 2 -C 4 dialkylamino;

R 3 is H, F, Cl, Br, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or CO 2 R 14 ;

R 4 is H, F, C 1 -C 4 alkyl, OH or OR 14 ;

R 3 and R 4 can be taken together with the carbon to which they are attached to form C(═O) or C(═NOR 14 );

R 5 is halogen, cyano, SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 - 4 haloalkoxy or S(O) n R 13 ;

R 6 and R 10 are independently H, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or S(O) n R 13 ;

R 7 is halogen, cyano, SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or S(O) n R 13 ;

R 8 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

R 9 is H, halogen, cyano, SF 5 , C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 4 alkenyloxy, C 3 -C 4 alkynyloxy or S(O) n R 13 ;

R 11 is H, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or S(O) n R 13 ;

R 12 is H, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or S(O) n R 13 ;

each R 13 is independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;

each R 14 is independently C 1 -C 4 alkyl; and

each n is independently 0, 1 or 2.

In the above recitations, the term “alkyl”, used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers. The term “1-2 alkyl” indicates that one or two of the available positions for that substituent may be alkyl which are independently selected. “Alkenyl” includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. “Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. “Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. “Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. “Alkoxyalkyl” denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 . “Alkenyloxy” includes straight-chain or branched alkenyloxy moieties. Examples of “alkenyloxy” include H 2 C═CHCH 2 O, (CH 3 ) 2 C═CHCH 2 O, (CH 3 )CH═CHCH 2 O, (CH 3 )CH═C(CH 3 )CH 2 O and CH 2 ═CHCH 2 CH 2 O. “Alkynyloxy” includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC≡CCH 2 O, CH 3 C≡CCH 2 O and CH 3 C≡CCH 2 CH 2 O. “Alkylthio” includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. “Alkylthioalkyl” denotes alkylthio substitution on alkyl. Examples of “alkylthioalkyl” include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 . “Alkylsulfinyl” includes both enantiomers of an alkylsulfinyl group. Examples of “alkylsulfinyl” include CH 3 S(O), CH 3 CH 2 S(O), CH 3 CH 2 CH 2 S(O), (CH 3 ) 2 CHS(O) and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers. Examples of “alkylsulfonyl” include CH 3 S(O) 2 , CH 3 CH 2 S(O) 2 , CH 3 CH 2 CH 2 S(O) 2 , (CH 3 ) 2 CHS(O) 2 and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. “Alkylamino”, “dialkylamino”, “alkenylthio”, “alkenylsulfinyl”, “alkenylsulfonyl”, “alkynylthio”, “allynylsulfinyl”, “alkynylsulfonyl”, and the like, are defined analogously to the above examples. One skilled in the art will appreciate that not all nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

The term “halogen”, either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. The term “1-2 halogen” indicates that one or two of the available positions for that substituent may be halogen which are independently selected. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F 3 C, ClCH 2 , CF 3 CH 2 and CF 3 CCl 2 . Examples of “haloalkoxy” include CF 3 O, CCl 3 CH 2 O, HCF 2 CH 2 CH 2 O and CF 3 CH 2 O.

The total number of carbon atoms in a substituent group is indicated by the “C i -C j ” prefix where i and j are numbers from 1 to 4. For example, C 1 -C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl; C 2 alkoxyalkyl designates CH 3 OCH 2 ; C 3 alkoxyalkyl designates, for example, CH 3 CH(OCH 3 ), CH 3 OCH 2 CH 2 or CH 3 CH 2 OCH 2 ; and C 4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH 3 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 . Examples of “alkylcarbonyl” include C(O)CH 3 , C(O)CH 2 CH 2 CH 3 and C(O)CH(CH 3 ) 2 . Examples of “alkoxycarbonyl” include CH 3 OC(═O), CH 3 CH 2 OC(═O), CH 3 CH 2 CH 2 OC(═O), (CH 3 ) 2 CHOC(═O) and the different butoxy- or pentoxycarbonyl isomers. In the above recitations, when a compound of Formula I is comprised of one or more heterocyclic rings, all substituents are attached to these rings through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.

When a group contains a substituent which can be hydrogen, for example R 9 , then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.

The compounds of this invention thus include compounds of Formula I, geometric and stereoisomers thereof, N-oxides thereof, and agriculturally suitable salts thereof. The compound of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.

The salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.

Preferred compounds of the invention for reasons of better activity and/or ease of synthesis are:

Preferred 1. Compounds of Formula I above, geometric or stereoisomers thereof, N-oxides thereof and agriculturally-suitable salts thereof, wherein

R 1 and R 2 are independently H, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;

R 5 and R 7 are independently halogen, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy or S(O) n R 13 ;

R 6 is H or F;

R 8 is C 1 -C 4 alkyl;

R 9 is halogen, cyano, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or S(O) n R 13 ;

R 10 is H, halogen, cyano or C 1 -C 4 haloalkyl;

R 11 is H, halogen, cyano or C 1 -C 4 haloalkyl;

R 12 is H, halogen, cyano or C 1 -C 4 haloalkyl; and

n is 0.

Preferred 2. Compounds of Preferred 1 wherein

W is N;

R 5 and R 7 are independently C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy; and

R 9 is halogen, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl or S(O) n R 13 .

Preferred 3. Compounds of Preferred 2 wherein

R 1 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy;

R 2 is H;

R 3 and R 4 are independently H, F or methyl;

R 5 and R 7 are independently C 1 -C 2 haloalkyl or C 1 -C 2 haloalkoxy; and

R 9 is C 1 -C 2 haloalkoxy, C 1 -C 2 haloalkyl or S(O) n R 13 .

Preferred 4. Compounds of Preferred 3 wherein

J is J-1, J-5 or J-7.

Preferred 5. Compounds of Preferred 2 wherein

R 3 and R 4 can be taken together with the carbon to which they are attached to form C(═O).

Preferred 6. Compounds of Preferred 5 wherein

R 1 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy;

R 2 is H;

R 5 and R 7 are independently C 1 -C 2 haloalkyl or C 1 -C 2 haloalkoxy; and

R 9 is C 1 -C 2 haloalkoxy, C 1 -C 2 haloalkyl or S(O) n R 13 .

Preferred 7. Compounds of Preferred 5 wherein

J is J-1 or J-5.

Most preferred is the compound of Formula I selected from the group consisting of:

(a) 5-ethyl-4-[[3-(trifluoromethoxy)phenyl]methyl]-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine;

(b) 5-ethyl-4-[[3-(trifluoromethyl)phenyl]methyl]-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine;

(c) 5-methyl-2-[4-(trifluoromethyl)phenyl]-4-[[3-(trifluoromethyl)phenyl]methyl]pyrimidine;

(d) 5-methyl-4-[[3-(trifluoromethoxy)phenyl]methyl]-2-[4-(trifluoromethyl)phenyl]pyrimidine;

(e) 5-methyl-4-[[3-(trifluoromethoxy)phenyl]methyl]-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine;

(f) [5-methyl-2-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl][3-(trifluoromethyl)phenyl]methanone;

(g) [5-methyl-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-4-pyrimidinyl][3-(trifluoromethyl)phenyl]methanone; and

(h) 5-methyl-4-[[3-(trifluoromethyl)phenyl]methyl]-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine.

This invention also relates to herbicidal compositions comprising herbicidally effective amounts of the compounds of the invention and at least one of a surfactant, a solid diluent or a liquid diluent. The preferred compositions of the present invention are those which comprise the above preferred compounds.

This invention also relates to a method for controlling undesired vegetation comprising applying to the locus of the vegetation herbicidally effective amounts of the compounds of the invention (e.g., as a composition described herein). The preferred methods of use are those involving the above preferred compounds.

The compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-12. The definitions of J, A, W, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , and R 14 in the compounds of Formulae 1-16 below are as defined above in the Summary of the Invention. Compounds of Formulae Ia-Ic are various subsets of the compounds of Formula I, and all substituents for Formulae Ia-Ic are as defined above for Formula I.

Scheme 1 illustrates the preparation of compounds of Formula Ia (Formula I wherein A is A-1). Substituted heterocycles of Formula 1 (where L 1 is halogen) can be coupled with metalated aryls or heteroaryls of Formula 2 (where Met is Sn(alkyl) 3 , B(OH) 2 or Zn(L 1 ) 2 ) in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O) or in the presence of a palladium(II) catalyst such as dichlorobis(triphenylphosphine)palladium(II) to provide compounds of Formula Ia. Palladium(II) catalysts are generally used with a suitable base such as aqueous sodium bicarbonate or sodium carbonate. Suitable solvents for this coupling include N,N-dimethylformamide, dimethoxyethane, acetonitrile or tetrahydrofuran. Reaction temperatures range from 20° C. to 130° C.

Scheme 2 illustrates the preparation of compounds of Formula Ib (Formula I wherein A is A-2). Substituted heterocycles of Formula 1 are allowed to react with substituted azoles of Formula 3 in the presence of a suitable base such as an alkali carbonate, alkali hydroxide, or alkali hydride in a solvent such as N,N-dimethylfornamide, acetonitrile or tetrahydrofuran at temperatures ranging from 0° C. to 130° C. to provide compounds of Formula Ib.

Scheme 3 illustrates a method for preparing compounds of Formula Ic wherein J is an azole heterocycle of Formula J-7 and A is A-1 or A-2. Compounds of Formula 4 are allowed to react with an azole heterocycle of Formula 3 in a protic or aprotic solvent at temperatures ranging from 0° C. to 100° C. in the presence of a suitable base such an alkali carbonate, alkali hydroxide, or alkali hydride to provide compounds of Formula Ic. Particularly suitable are potassium carbonate as base and acetonitrile or N,N-dimethylformamide as solvent at a reaction temperature range of 20° C. to 80° C.

Substituted pyrimidine intermediates of Formula 1 (wherein J is J-1 to J-6) can be prepared by the method shown in Scheme 4. By the synthetic protocol of Menta, E. and Oliva, A. J. Heterocyclic Chem. (1997), 34, p 27, a dihalopyrimidine of Formula 5 (where L 1 and L 2 are halogen) is coupled with a substituted alkyl zinc reagent of Formula 6 (where L 3 is halogen) in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O) or in the presence of a palladium(II) catalyst such as dichloro-bis(triphenylphosphine)palladium(II). Palladium(II) catalysts are generally used with a suitable base such as sodium bicarbonate or sodium carbonate. Suitable solvents for this coupling include N,N-dimethylformamide, dimethoxyethane, acetonitrile or tetrahydrofuran. Reaction temperatures range from 0° C. to 130° C.

Metalated aryls and heteroaryls of Formula 2 can be obtained commercially or can be prepared by methods known in the art: Sandosham, J. and Undheim, K. Tetrahedron (1994), 50, pp 275-284; Undheim, K. and Benneche, T. Acta Chemica Scandinavica (1993), 47, pp 102-121; Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1995; volume 62, pp 305-418.

Azoles of Formula 3 can be obtained commercially or can be prepared by methods known in the art Elguero, J. et al., Organic Preparations and Procedures Int. (1995), 27, pp 33-74; Comprehensive Heterocyclic Chemistry; Potts, K., Ed.; Pergamon Press: New York, 1984; volume 5, chapters 4.04-4.13; Heterocyclic Compounds; Elderfield, R., Ed.; John Wiley: New York, 1957; volume 5, chapters 2 and 4; Baldwin, J. et al. J. Med. Chem., (1975), 18, pp 895-900; Evans, J. J. et al. U.S. Pat. No. 4,038,405.

Dihaloheterocycles of Formula 5 can be obtained commercially or can be readily prepared by known methods in the art; for example, see Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1993; volume 58, pp 301-305; Heterocyclic Compounds; Elderfield, R. C., Ed.; John Wiley: New York, 1957; volume 6, chapter 7, pp 265-270.

Zinc reagents of Formula 6 can be made by the method shown in Scheme 5. A substituted alkyl halide of Formula 7 (where L 3 is halogen) is allowed to react with activated zinc (see Jubert, C. and Knochel, P. J. Org. Chem. (1992), 57, p 5425; Knochel, P. and Singer, R. D. Chem. Rev. (1993), 93, p 2117) in a suitable solvent such as N,N-dimethylformamide, dimethoxyethane, acetonitrile or tetrahydrofuran. Reaction temperatures range from 0° C. to 130° C.

As shown in Scheme 6, heterocyclic benzylic bromides of Formula 4 can be made by bromination of heterocycles of Formula 8 with bromine in an acidic solvent such as acetic acid at temperatures ranging from 20° C. to 100° C. (see, for example, Strekowski et al. J. Org. Chem. (1992), 56, p 5610).

Heterocycles of Formula 8 can be made from precursor heterocycles of Formula 9 as shown in Scheme 7. The addition of lithium or Grignard reagents of formula R 3 R 4 CHLi or R 3 R 4 CHMgL 1 to heterocycles of Formula 9 is carried out in ethereal solvents such as ether or tetrahydrofuran at temperatures ranging from −70° C. to 30° C. The reaction mixture is worked up by the addition of water and an oxidizing agent. A particularly suitable oxidizing agent is dichlorodicyanoquinone (DDQ). See Strekowski et al. J. Org. Chem. (1992), 56, p 5610 for examples of this synthetic method.

Heterocycles of Formula 9 can be prepared according to methods taught by Strekowski et al. J. Org. Chem. (1992), 56, p 5610; Bredereck et. al., Chem. Ber. (1960), 93, p 1208; Burdeska et al. Helv. Chim. Acta (1981), 64, p 113; Undheim, K. and Benneche, T. Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1995, volume 62, pp 305-418; and Comprehensive Heterocyclic Chemistry; Boulton, A. J., and McKillop, A., Eds.; Pergamon Press: New York, 1984; volume 3, chapter 2.13. Lithium and Grignard reagents of formulae R 3 R 4 CHLi or R 3 R 4 CHMgL 1 are commercially available or can be prepared by methods well known in the art.

Compounds of Formula 1 (wherein R 3 and R 4 are taken together as C(═O)) can be prepared by the condensation of pyrimidines and pyridines of Formula 10 with aldehydes of Formula 11 in the presence of an imidazolium catalyst of Formula 12 as shown in Scheme 8. This reaction is carried out in the presence of a strong base such as an alkali hydride, preferably sodium hydride, in solvents such as dichloromethane, dioxane, tetrahydrofuran, benzene, toluene or other aprotic solvent. The reaction may be carried out at temperatures between 0 and 120° C. A wide variety of azolium salts are known to catalyze this transformation; see, for example, Miyashita Heterocycles, (1996), 43, 509-512 and references cited therein. A preferred catalyst is 1,3-dimethylimidazolium iodide.

Compounds of Formula I (wherein R 3 and R 4 are taken together as C(═NOR 14 )) can be formed directly from compounds of Formula I (wherein R 3 and R 4 are taken together as C(═O)) by the action of hydroxylamine or capped hydroxylamine salts of Formula 13 as shown in Scheme 9. Many hydroxylamines are commercially available as acid salts and are freed by the action of a base in the presence of the ketone of Formula I. Suitable bases include alkali carbonates, acetates, and hydroxides. These reactions are best carried out in protic solvents, such as lower alcohols, at temperatures between 0 and 120° C. Especially preferred conditions use sodium carbonate or sodium acetate as base in ethanol at 70 to 80° C.

Compounds of Formula I (wherein R 3 is OH and R 4 is H) can be made by the reduction of ketones of Formula I (wherein R 3 and R 4 are taken together as C(═O)) as shown in Scheme 10. A wide variety of reduction conditions can be utilized, but for reasons of ease of use and selectivity, alkali borohydrides are preferred reductants. The reduction can be carried out at 0 to 100° C. in a variety of solvents which are inert to the action of borohydrides. Especially preferred conditions are the use of sodium borohydride in ethanol at 0 to 25° C.

As shown in Scheme 11, compounds of Formula 1 wherein J is J-7 can also be made via the bromination of compounds of Formula 14 with molecular bromine in an acidic solvent such as acetic acid at temperatures ranging from 20 to 100° C. in the same way as previously described in Scheme 6. The brominated products of Formula 15 can be displaced by heterocycles of Formula 3 in the presence of a base such as potassium carbonate as previously described for Scheme 2. Compounds of Formula 14 are known in the literature or are commercially available. See Benneche ( Acta Chemica Scandanavia, 1997, 51, 302) for preparation of these compounds from compounds of Formula 5.

Compounds of Formula 1 in which R 3 is cyano can be made as shown in Scheme 12. The reaction of acetonitrile derivatives of formula 16 with compounds of Formula 5 in the presence of a base gives compounds of formula 1 with a cyano group. The reaction can be carried out in a variety of solvents such as dimethylformamide, tetrahydrofuran, or other solvents inert to strong bases. A wide variety of bases which can deprotonate substituted acetonitriles can be used. Sodium hydride and potassium t-butoxide are preferred due to their ease of use and availability. The reaction can be carried out at temperatures ranging from 0 to 100° C. Compounds of formula 16 are well known in the literature and many are commercially available

Compounds of Formula I substituted with the group S(O) n R 13 wherein n is 1 or 2 can be prepared from compounds of Formula I substituted with said S(O) n R 13 group wherein n is 0 by treatment with an oxidizing reagent such as m-chloroperoxybenzoic acid or Oxone® (potassium peroxymonosulfate). This type of oxidation reaction is well known in the art; for example, see March, J. Advanced Organic Chemistry; John Wiley: New York, 1992; 4 th edition, pp 1201-1203.

It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula I.

One skilled in the art will also recognize that compounds of Formula I and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.

Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1 H NMR spectra are reported in ppm downfield from tetramethylsilane; s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, br s=broad singlet.

To a suspension of zinc dust (2.5 g, 38 mmol) stirred in 25 mL of tetrahydrofuran were added 2 drops of 1,2-dibromoethane and the mixture was heated to reflux. The suspension was then cooled and 2 drops of trimethylsilyl chloride were added followed by portionwise addition of 3-(trifluoromethyl)benzyl bromide (6.0 g, 25 mmol) with heating. When the reaction temperature reached 55° C., a strong exotherm occurred and the reaction mixture was allowed to heat at reflux. The cooled reaction solution was decanted into a solution of 2,4dichloro-5-methylpyrimidine (3.3 g, 20 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.44 g, 0.63 mmol) stirring in 15 mL of tetrahydrofuran. Upon heating, the reaction mixture exothermed strongly again at 55° C. and was then heated to reflux. The reaction mixture was allowed to cool and partitioned between diethyl ether and water. The organic layer was separated, washed with 1 N aqueous hydrochloric acid and brine, dried over magnesium chloride and concentrated under reduced pressure to give a crude oil. Purification by flash chromatography on silica gel (15 to 25% ethyl acetate in hexane) yielded 2.4 g of the title compound of Step A as an oil. 1 H NMR (CDCl 3 ): δ8.35 (s, 1H), 7.60-7.35 (m, 4H), 4.15 (s, 2H), 2.25 (s, 3H).

Step B: Preparation of 5-methyl-2-[4-(trifluoromethyl)phenyl]-4-[[3-(trifluoromethyl)phenyl]methyl]pyrimidine

A stirred mixture of 4-(trifluoromethyl)benzene boronic acid (430 mg, 2.3 mmol), the title compound of Step A (500 mg, 1.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (120 mg, 0.17 mmol) and sodium carbonate (550 mg, 5.2 mmol) in a mixture of 6 mL of water and 2 mL of tetrahydrofuran was heated at reflux for 1.5 h. The reaction mixture was then partitioned between diethyl ether and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (20 to 25% ethyl acetate in hexane) followed by trituration with 10% diethyl ether in hexane afforded 350 mg of the title compound of Step B, a compound of this invention, as a yellow-tinted solid melting at 112-113° C. 1 H NMR (CDCl 3 ): δ8.55 (m, 3H), 7.70 (d, 2H), 7.60 (s, 1H), 7.55-7.40 (m, 3H), 4.25 (s, 2H), 2.30 (s, 3H).

Step A: Preparation of 5-methyl-4-[[3-(trifluoromethyl)phenyl]methyl]-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine

A stirred mixture of 3-(trifluoromethyl)pyrazole (390 mg, 2.9 mmol), the title compound of Step A in Example 1 (750 mg, 2.6 mmol), and powdered potassium carbonate (1.1 g, 7.9 mmol) in 10 mL of N,N-dimethylformamide was heated at 60° C. for 3 h followed by heating at 80° C. for 1 h. The reaction mixture was then partitioned between diethyl ether and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (5% diethyl ether in 1-chlorobutane) afforded 210 mg of the title compound of Step A as an oil which solidified to a white solid melting at 90-92° C. 1 H NMR (CDCl 3 ): δ8.55 (t,2H), 7.55-7.50 (m, 2H), 7.45-7.40 (m, 2H), 6.72 (d, 1H), 4.26 (s, 2H), 2.32 (s, 3H).

A sample of 4-trifluoromethylbenzamidine hydrochloride dihydrate (Maybridge, 15.2 g, 58 mmol) was dissolved in 100 mL of methanol and 3-ethoxy-2-methylacrolein (Janssen, 7.8 g, 64 mmol) was added. Sodium methoxide (25% solution in methanol, 14.7 mL) was added and the mixture was heated at 50° C. for 3 h. The cooled reaction mixture was then dded to 500 ml of ice water and stirred for 30 minutes. The white solid was filtered, air dried, dissolved in 300 mL of dichloromethane and dried over magnesium sulfate. The solvent was removed under reduced pressure to yield, after trituration with hexanes, 12.5 g of the product as a white solid melting at 143-146° C. 1 H NMR (CDCl 3 ): δ2.37 (s, 3H), 7.73 (d, 2H), 8.53 (d, 2H), 8.66 (s, 2H).

The title compound of Step A (9.0 g, 38 mmol) was dissolved in 50 mL of tetrahydrofuran and treated with methyl lithium (1.4 M in ether, 34 mL, 47 mmol) at a temperature of −70° C. The reaction mixture exothermed to −35° C. The mixture was stirred at −30° C. for 1.5 h and then treated with 1 mL of water and dichlorodicyanoquinone (9.44 g, 42 mmol). The mixture was stirred at 25° C. for 30 minutes and then partitioned twice between 100 mL of water and 100 mL of dichloromethane. The combined organics were washed with brine and dried over magnesium sulfate. The residue after evaporation was subjected to silica gel chromatography using hexanes/ethyl acetate (95:5) as eluent to give 9.02 g of the title compound of Step B as a white solid melting at 128-131° C. 1 H NMR (CDCl 3 ): δ2.31 (s, 3H), 2.56 (s, 3H), 7.71 (d, 2H), 8.49 (d, 2H), 8.53 (s, 1H).

The title compound of Step B (2.0 g, 8 mmol) was dissolved in 10 mL of acetic acid and treated with bromine (0.4 mL, 8 mmol). The mixture was heated at 80° C. until the orange color was discharged (1 h). The mixture was evaporated under reduced pressure, diluted with 50 mL of ether and washed twice with 50 mL of sodium bicarbonate and then 50 mL of brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to yield 2.54 g of the title compound of Step C as a tan solid which was used immediately in the next step without further purification. 1 H NMR (CDCl 3 ): δ2.44 (s, 3H), 4.54 (s, 2H), 7.74 (d, 2H), 8.56 (d, 2H), 8.62 (s, 1H).

Step D: Preparation of 5-methyl-2-(4-trifluoromethylphenyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]methylpyrimidine

The title compound of Step C (0.7 g, 2 mmol), 3-trifluoromethylpyrazole (0.27 g, 2 mmol) and potassium carbonate (0.83 g, 6 mmol) were suspended in 10 mL of acetonitrile and heated to reflux for 1 h. The salts were filtered and the acetonitrile was removed under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (85:15) to afford 0.52 g of the title compound of Step D, a compound of this invention, as a white solid melting at 112-114° C. 1 H NMR (CDCl 3 ): δ2.39 (s, 3H), 5.53 (s, 2H), 6.62 (d, 1H), 7.6-7.8 (m, 3H), 8.44 (d, 2H), 8.6 (s, 1H).

2,4-Dichloro-5-methylpyrimidine (3.6 g, 18.4 mmol) was dissolved in dichloromethane (50 mL) and treated sequentially with 3-trifluoromethylbenzaldehyde (3.3 g, 18.4 mmol), and 1,3-dimethylimidazolium iodide (1.37 g, 6.2 mmol). Sodium hydride (0.74 g, 18.4 mmol) was added and an exotherm was noted. After being heated at reflux for 3 h, the reaction was quenched with water and the layers were separated. The dried (magnesium sulfate) organic layer was purified by chromatography on silica gel using hexanes/ethyl acetate 85:15 as eluent. The title compound of Step A (1.8 g) was isolated as a white solid melting at 113-116° C. 1 H NMR (CDCl 3 /200 MHz) 2.39 (s, 3H), 7.66 (m, 1H), 7.90 (d, 1H), 8.07 (s,1H), 8.69 (s, 1H).

Step B: Preparation of [5-methyl-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-4-pyrimidinyl][3-(trifluoromethyl)phenyl]methanone

The title compound of Step A (0.6 g, 2 mmol), 3-trifluoromethylpyrazole (0.25 g), and potassium carbonate (0.8 g, 6 mmol) were suspended in acetonitrile (15 mL) and heated at reflux for 3 h. The cooled reaction mixture was filtered and the cake washed with acetonitrile. After evaporation of the solvent under reduced pressure, the residue was subjected to silica gel chromatography using hexanes/ethyl acetate (85:15) to give 0.12 g of the title compound of Step B, a compound of the invention, as a white solid. 1 H NMR (CDCl 3 /200 MHz) 2.45 (s, 3H), 6.75 (d, 1H), 7.67 (d, 1H), 7.92 (d, 1H), 8.10 (s, 1H), 8.27 (s, 1H), 8.54 (d, 1H), 8.9 (s, 1H).

Seeds of barnyardgrass ( Echinochloa crus - galli ), crabgrass (Digitaria spp.), morningglory (Ipomoea spp.), and velvetleaf ( Abutilon theophrasti ) were planted into a sandy loam soil and treated preemergence by soil drench with test chemicals formulated in a non-phytotoxic solvent mixture which includes a surfactant. At the same time, these crop and weed species were also treated postemergence sprayed to runoff, with test chemicals formulated in the same manner.

Plants ranged in height from two to eighteen cm and were in the one to two leaf stage for the postemergence treatment. Treated plants and untreated controls were maintained in a greenhouse for approximately eleven days, after which all treated plants were compared to untreated controls and visually evaluated for injury. Plant response ratings, summarized in Table A, are based on a 0 to 10 scale where 0 is no effect and 10 is complete control. A dash (−) response means no test results.

Seeds of bedstraw ( Galium aparine ), blackgrass ( Alopecurus myosuroides ), broadleaf signalgrass ( Brachiaria decumbens ), cocklebur ( Xanthium strumarium ), corn ( Zea mays ), crabgrass ( Digitaria sanguinalis ), giant foxtail ( Setaria faberii ), lambsquarters ( Chenopodium album ), momingglory ( Ipomoea hederacea ), pigweed ( Amaranthus retroflexus ), rape ( Brassica napus ), soybean ( Glycine max ), sugar beet ( Beta vulgaris ), velvetleaf ( Abutilon theophrasti ), wheat ( Triticum aestivum ), wild oat ( Avena fatua ) and purple nutsedge ( Cyperus rotundus ) tubers were planted and treated preemergence with test chemicals formulated in a non-phytotoxic solvent mixture which included a surfactant.

At the same time, these crop and weed species were also treated with postemergence applications of test chemicals formulated in the same manner. Plants ranged in height from 2 to 18 cm (1- to 4-leaf stage) for postemergence treatments. Plant species in the flood test consisted of rice ( Oryza sativa ), smallflower flatsedge ( Cyperus difformis ), duck salad ( Heteranthera limosa ) and bamyardgrass ( Echinochloa crus - galli ) grown to the 2-leaf stage for testing. Treated plants and controls were maintained in a greenhouse for twelve to sixteen days, after which all species were compared to controls and visually evaluated. Plant response ratings, summarized in Table B, are based on a scale of 0 to 10 where 0 is no effect and 10 is complete control. A dash (−) response means no test result.

Compounds evaluated in this test were formulated in a non-phytotoxic solvent mixture which included a surfactant and applied to plants that were grown for various periods of time before treatment (postemergence application) using a sandy loam soil mixture.

Plantings of these crops and weed species were adjusted to produce plants of appropriate size for the postemergence test. All plant species were grown using normal greenhouse practices. Crop and weed species include arrowleaf sida ( Sida rhombifolia ), barnyardgrass ( Echinochloa crus - galli ), cocklebur ( Xanthium strumarium ), common ragweed ( Ambrosia elatior ), corn ( Zea mays ), cotton ( Gossypium hirsutum ), eastern black nightshade ( Solanum ptycanthum ), fall panicum ( Panicum dichotomiflorum ), field bindweed ( Convolvulus arvensis ), giant foxtail ( Setaria faberii ), hairy beggarticks ( Bidens pilosa ), ivyleaf morningglory ( Ipomoea hederacea ), johnsongrass ( Sorghum halepense ), ladysthumb smartweed ( Polygonum persicaria ), lambsquarters ( Chenopodium album ), large crabgrass ( Digitaria sanguinalis ), purple nutsedge ( Cyperus rotundus ), redroot pigweed ( Amaranthus retroflexus ), soybean ( Glycine max ), surinam grass ( Brachiaria decumbens ), velvetleaf ( Abutilon theophrasti ) and wild poinsettia ( Euphorbia heterophylla ).

Treated plants and untreated controls were maintained in a greenhouse for approximately 14 to 21 days, after which all treated plants were compared to untreated controls and visually evaluated. Plant response ratings, summarized in Table C, were based upon a 0 to 100 scale where 0 was no effect and 100 was complete control. A dash response (−) means no test result.

Compounds evaluated in this test were formulated in a non-phytotoxic solvent mixture which included a surfactant and applied to plants that were in the 1- to 4-leaf stage (postemergence application). A mixture of sandy loam soil and greenhouse potting mix in a 60:40 ratio was used for the postemergence test.

Plantings of these crops and weed species were adjusted to produce plants of appropriate size for the postemergence test. All plant species were grown using normal greenhouse practices. Crop and weed species include alfalfa ( Medicago sativa ), annual bluegrass ( Poa annua ), blackgrass ( Alopecurus myosuroides ), black nightshade ( Solanum nigra ), chickweed ( Stellaria media ), common poppy ( Papaver rhoeas ), deadnettle ( Lamium amplexicaule ), downy brome ( Bromus tectorum ), field violet ( Viola arvensis ), galium 2 ( Galium aparine ), green foxtail ( Setaria viridis ), Italian ryegrass ( Lolium multiflorum ), jointed goatgrass ( Aegilops cylindrica ), kochia ( Kochia scoparia ), lambsquarters ( Chenopodium album ), lentil ( Lens culinaris ), littleseed canarygrass ( Phalaris minor ), pea ( Pisum sativum ), potato ( Solanum tuberosum ), rape ( Brassica napus ), redroot pigweed ( Amaranthus retroflexus ), Russian thistle ( Salsola kali ), scentless chamomile ( Matricaria inodora ), sorghum ( Sorghum vulgare ), spring barley ( Hordeum vulgare ), sugar beet ( Beta vulgaris ), sunflower ( Helianthus annuus ), ivyleaf speedwell ( Veronica hederaefolia ), spring wheat ( Triticum aestivum ), winter wheat ( Triticum aestivum ), wild buckwheat ( Polygonum convolvulus ), wild mustard ( Sinapis arvensis ), wild oat ( Avena fatua ), windgrass ( Apera spica - venti ) and winter barley ( Hordeum vulgare ).

Treated plants and untreated controls were maintained in a greenhouse for approximately 21 to 28 days, after which all treated plants were compared to untreated controls and visually evaluated. Plant response ratings, summarized in Table D, are based upon a 0 to 100 scale where 0 is no effect and 100 is complete control. A dash response (−) means no test result.

Seeds, tubers, or plant parts of alexandergrass ( Brachiaria plantaginea ), annual bluegrass ( Poa annua ), arrowleaf sida ( Sida rhombifolia ), barnyardgrass ( Echinochloa crus - galli ), bermudagrass ( Cynodon dactylon ), citrus ( Citrus sinensis ), common chickweed ( Stellaria media ), common purslane ( Portulaca oleracea ), common ragweed ( Ambrosia elatior ), common groundsel ( Senecio vulgaris ), dallisgrass ( Paspalum dilatatum ), goosegrass ( Eleusine indica ), green foxtail ( Setaria viridis ), guineagrass ( Panicum maximum ), itchgrass ( Rottboellia exaltata ), johnson grass ( Sorghum halepense ), kochia ( Kochia scoparia ), large crabgrass ( Digitaria sanguinalis ), leafy spurge ( Euphorbia esula ), pitted morningglory ( Ipomoea lacunosa ), purple nutsedge ( Cyperus rotundus ), quackgrass ( Agropyron repens ), Russian thistle ( Salsola kali ), sandbur ( Cenchrus echinatus ), sourgrass ( Trichachne insularis ), Spanishneedles ( Bidens bipinnata ), sugarcane ( Saccharum officinarum ), surinam grass ( Brachiaria decumbens ) and tall mallow ( Malva sylvestris ) were planted into greenhouse pots of flats containing greenhouse planting medium. Plant species were grown grown in separate pots or individual compartments. Preemergence applications were made within one day of planting the seed or plant part. Postemergence applications were applied when the plants were in the two to four leaf stage (three to twenty cm).

Test chemicals were formulated in a non-phytotoxic solvent mixture which included a surfactant and applied preemergence to the soil surface, postemergence to the plants or as a post directed spray to plants and soil at the base of the target species. Untreated control plants and treated plants were placed in the greenhouse and visually evaluated for injury 13 to 21 days after herbicide application. Plant response ratings, summarized in Table E, are based on a 0 to 100 scale where 0 is no injury and 100 is complete control. A dash (−) response means no test result.