WO2001079203A1 - Herbicidal 3-heterocyclic substituted benzisothiazole and benzisoxazole compounds - Google Patents

Herbicidal 3-heterocyclic substituted benzisothiazole and benzisoxazole compounds Download PDF

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Publication number
WO2001079203A1
WO2001079203A1 PCT/EP2001/004356 EP0104356W WO0179203A1 WO 2001079203 A1 WO2001079203 A1 WO 2001079203A1 EP 0104356 W EP0104356 W EP 0104356W WO 0179203 A1 WO0179203 A1 WO 0179203A1
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Prior art keywords
methyl
trifluoromethyl
uracil
benzisothiazol
alkyl
Prior art date
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PCT/EP2001/004356
Other languages
French (fr)
Inventor
Peter John Wepplo
Richard Anthony Rampulla
Gavin David Heffernan
Michael Vernie Cosette
Charles Malcolm Langevine
Venkataraman Kameswaran
Robert Eugene Diehl
James Joseph Fiordeliso
Gregory Jay Haley
Michael Anthony Guaciaro
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Basf Aktiengesellschaft
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Publication date
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to JP2001576802A priority Critical patent/JP2004501084A/en
Priority to AU2001263864A priority patent/AU2001263864A1/en
Priority to EP01938123A priority patent/EP1274708A1/en
Priority to CA002408396A priority patent/CA2408396A1/en
Publication of WO2001079203A1 publication Critical patent/WO2001079203A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/86—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • WO 99/14216 also discloses benzisothiazol-substituted uracil compounds and their use as herbicides.
  • the present invention provides compounds of formula I
  • R is halogen , Ci-C ⁇ -alkyl , Ci-C ⁇ -haloalkyl , C 3 -C 7 -cycloalkyl , C 2 -C6-alkenyl , C 2 -C6-haloalkenyl , C 3 -C6-alkynyl , cyano , benzyl , hydroxyl , amino , C -C6-cyanoalkyl;
  • R i is hydrogen, halogen, Ci-C ⁇ -alkyl, C ⁇ -C 6 -haloalkyl, C 3 -C 7 - cycloalkyl, C 2 -C 6 -alkenyl, C 2 -Cg-haloalkenyl, C 3 -C 6 ⁇ al- kynyl, cyano, benzyl, hydroxyl, amino, C 2 -C 6 -cyanoalkyl or R and R l , together with the other atoms to which they are attached, form a four to seven-membered ring optionally interrupted by oxygen, sulfur or nitrogen and optionally substituted with one to three methyl groups or one or more halogen atoms;
  • R 2 and R 3 are, independently of one another, hydrogen, halogen,
  • R 2 and R 3 together with the atoms to which they are attached, form a four to seven-membered saturated or unsaturated ring optionally interupted by oxygen, sulfur or nitrogen and optionally substituted with one to three methyl groups or one or more halogen atoms;
  • R 4 , R 6 and R 7 are each independently hydrogen, halogen or C ⁇ L -Ce-alkyl
  • R 5 is hydrogen, halogen, Ci-C ⁇ -alkyl, Ci-C ⁇ -haloalkyl, C 3 -C 7 - cycloalkyl, C 3 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 3 -Cg-al- kynyl, 0R i2 or SR X3 ;
  • R 8 , R 9 , R 12 , R 3 and R 14 are each independently of one another hydrogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 3 -C 6 -alkynyl, C 3 -C-cycloalkyl, c 2 _c 6 -cyanoalkyl, benzyl or optionally substituted phenyl;
  • R 10 is hydrogen, Ci-C ⁇ -alkyl, C ⁇ -C 6 -haloalkyl, optionally substituted phenyl or optionally substituted benzyl;
  • R U is C ⁇ -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 7 -cyclo- alkyl, Ci-C ⁇ -haloalkyl, benzyl, optionally substituted phenyl or S(0) n -R l4 ;
  • n is an integer of 0, 1 or 2 ;
  • A, Ai and A 2 are each independently oxygen or sulfur;
  • X is hydrogen, halogen or C ⁇ -C 4 -alkyl
  • ⁇ i is hydrogen, halogen, C ⁇ -C 4 -alkyl, C ⁇ -C-haloalkyl, C ⁇ -C 4 -alkoxy or C ⁇ -C 4 -haloalkoxy;
  • V is hydroxyl, halogen, C ⁇ -C 4 -alkoxy or C ⁇ -C -alkylthio
  • R 88 is cyano, C ⁇ -C-alkyl, C ⁇ -C 4 -haloalkyl, C ⁇ -C 4 -alkoxy,
  • R 89 is hydrogen, cyano, halogen, C ⁇ -C 4 -alkyl or C ⁇ -C 4 -haloalkyl,
  • Y is an optionally substituted three to seven-membered hetero- cyclic ring containing carbon and one to four heteroato s selected from oxygen, sulfur and nitrogen;
  • Z is oxygen or S(0) m ;
  • n is an integer of 0, 1 or 2;
  • the present invention further provides herbicidal compositions, and methods. DETAILED DESCRIPTION OF THE INVENTION
  • Preferred compounds I of the invention are those, wherein
  • Q is Q 7 or Q 24 ;
  • R is C ⁇ -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 6 -alkynyl or amino;
  • R 2 is C ⁇ -C 6 -alkyl or C ⁇ -C 6 -haloalkyl;
  • R 3 is hydrogen;
  • Y is selected from
  • R i5 , R i8 , R 20 and R i are each independently hydrogen, C ⁇ -C 8 -alkyl, Ci-C ⁇ -haloalkyl, C ⁇ -Ca-alkoxy, C ⁇ -C 8 -thioalkyl, halogen, nitro, cyano, hydroxy, C 2 -C 6 -alkenyl, C 3 -Cg-alkynyl, C -C 6 -haloalkenyl, C 3 -Cg-cycloalkyl or R 20 and the carbon on Y to which R 20 is attached may form an exocyclic double bond or when R 20 and R 21 are attached to the same carbon of Y 25 , R 20 , R 2i and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring;
  • R i6 is hydrogen, halogen, C ⁇ -C 8 -alkyl optionally substituted with C(0)R 22 , CO-OR 23 , X 2 R24, S(0) m -alkyl, NR 86 R 87 ,
  • R i? is hydrogen, C ⁇ -C 8 -alkyl, C 2 -C 8 -alkenyl, C 3 -C 6 -alkynyl, C(0)R 25 or optionally substituted benzyl;
  • Rl9, R 29 , R33, R34 f R 35, R 37, R 38, R 39 f R 42 , R 43, R 44 R 46, R 47 f R 48, R50, R 51 f R 52, R 53 f R 55 R 56 R 57 f R 60 f R 61, R 62 , R 64, R 65, R66, R69, R70, R 71, R 73, R 74 f R 75 f R 76, R 80 f R 85 a nd R86 are, independently of one another, hydrogen, hydroxy, C ⁇ -Cs-alkyl, C ⁇ -C 4 -alkoxy, C 3 -Cs-cycloalkyl, C 2 -C 8 -al- kenyl, C 3 -C 6 -alkynyl, optionally substituted phenyl or optionally substituted benzyl;
  • R 23 , R 26 , R 3i , R 40 , R 49 , R 58 , R 67 and R 79 are, independently of one another, hydrogen, C ⁇ -Cs-alkyl, C ⁇ -Cs-haloalkyl, C 3 -Cs- cycloalkyl, C 3 -C 8 -halocycloalkyl, C 2 -C 8 -alkenyl, C 2 -Cs- haloalkenyl, Cs-Cs-cycloalkenyl, Cs-Cs-halocycloalkenyl, C 3 -C 8 -alkynyl, C 3 -Cs-haloalkynyl, optionally substituted phenyl, optionally substituted benzyl, furfuryl, pyridyl, thienyl, an alkali metal, alkaline earth metal, manganese, copper, zinc, cobalt, silver, nickel, ammonium or organic ammonium cation
  • R 22 , R 2 5, R32, R 36, R 41, R 45 R 54, R 59, R 63, R 68, R 72, R 77, R 78, R 81 and R 87 are, independently of one another, hydrogen,
  • R 30 is hydroxy, C ⁇ -C 8 -alkyl, C 3 -C 8 -cycloalkyl, C ⁇ -Cs-haloalkyl, C 2 -Cs-alkenyl, C 2 -C 8 -haloalkenyl, C 3 -C 8 -alkynyl, optionally substituted phenyl, optionally substituted benzyl or NR 80 R 8l ;
  • B and ⁇ i are, independently of one another, oxygen, sulfur or NR i7 ;
  • X 2 and X 3 are, independently of one another, oxygen or sulfur;
  • Q is Q 24 ;
  • R is C ⁇ -C 3 -alkyl;
  • R 2 is C ⁇ -C 3 -haloalkyl
  • Z is sulfur;
  • Y is selected from ⁇ l, Y 2 , Y 3 , Y 4 , ⁇ 5, ⁇ 6, yi ⁇ f ⁇ ii f ⁇ i4 f ⁇ i5,
  • R i5 , R X8 , R 20 and R 2 ⁇ are, independently of one another, hydrogen, C ⁇ -C 3 -alkyl, C ⁇ -C 3 -haloalkyl, C ⁇ -C 3 -alkoxy, halogen, hydroxy or, when R 20 and R 21 are attached to the same carbon of Y 25 , an epoxide ring is formed;
  • R 16 is hydrogen, halogen, C ⁇ -C 3 -alkyl optionally substituted with C(0)R 22 , CO-OR 23 , ⁇ 2R24 or s(0) m -alkyl, or is phenyl; C ⁇ -C 3 -haloalkyl, C(0)R 25 , CO-OR 26 , ⁇ 3 27 f C 3 -C 8 -cycloalkyl, N(R 29 )-S0 2 -R 3 ° or C 2 -C 4 -alkenyl;
  • R l? is hydrogen, C ⁇ -C 3 -alkyl, C 2 -C 4 -alkenyl or C(0)R 25 ;
  • R 19 , R 29 and R 80 are, independently of one another, hydrogen or
  • R 22 , R 25 and R 8i are, independently of one another, hydrogen
  • R 23 , R 6 an d R 3I are, independently of one another, hydrogen, C ⁇ -C 3 -alkyl, C 2 -C 4 -alkenyl or C 3 -C 6 -alkynyl;
  • R 24 and R 27 are, independently of one another, hydrogen or C ⁇ -C 3 - alkyl optionally substituted with one CO-OR 3i group or one
  • R 30 is C ⁇ -C 3 -alkyl, C 3 -C 5 -cycloalkyl, C ⁇ -C 3 -haloalkyl, C 2 -C 4 -al- kenyl, optionally substituted phenyl, optionally substituted benzyl or NR 80 R 8l ;
  • X 2 and X 3 are, independently of one another, oxygen.
  • Y is selected from
  • Ri 5 , R i8 , R 20 and R 2X are, independently of one another, hydrogen, C -C 3 -alkyl, C ⁇ -C 3 -haloalkyl or C ⁇ -C 3 -alkoxy;
  • R i6 is hydrogen, halogen, C ⁇ -C8-alkyl optionally substituted with X 2 R 24 , C ⁇ -C 3 -haloalkyl, phenyl or C 2 -C 4 -alkenyl;
  • R 17 is hydrogen, methyl or C(0)R 25 ;
  • Ri 9 is hydrogen or C ⁇ -C 3 -alkyl
  • R 2 is hydrogen or C ⁇ -C 3 -alkyl
  • R 25 is C ⁇ -C 3 -alkyl or phenyl ;
  • X 2 is oxygen .
  • R 88 i preferably C ⁇ -C-haloalkyl, C ⁇ -C 4 -haloalkoxy or C ⁇ -C 4 -alkyl- sulfonyl, in particular trifluoromethyl or difluoromethoxy;
  • R 88 is preferably hydrogen or halogen, in particular chlorine or bromine.
  • Formula I compounds of the present invention which are particularly effective herbicidal agents include l-methyl-3-[ 3-( 3-thienyl ) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; ethyl (R)-2-[5-[3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl) -1 (2H) -pyrimidinyl]-1,2-benzisothiazol-3-yl] -4-thi- azolidinecarboxylate; l-methyl-3-[3-(2-thienyl) -1,2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 3-methyl-2-thienyl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; l-methyl-3-[3-( l-methylimid
  • 1,2-benzisothiazole-3-carboxaldehyde 5-[3 , 6-dihydro-3-methyl- 2, 6-dioxo-4-(trifluoromethyl ) -1 (2H) -pyrimidinyl]-, 3-[bis(2-hydroxyethyl) dithioacetal] ; l-methyl-3-[ 3-( 1 , 3-oxathian-2-yl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; l-methyl-3-[3-( 1 ,3-oxathian-2-yl)-1,2-benzisothiazol-5-yl]- 6-(trifluoromethyl)uracil S' ,S'-dioxide;
  • 6-( rifluoromethyl)uracil 3-[3-[ (4R,5S)-4,5-dimethyl-l,3-dioxolan-2-yl]-6-fluoro-1,2-benz- isothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
  • the compounds of formula I of the present invention are effective herbicidal agents useful for the control of a wide variety of undesirable plant species and for controlling weeds native to both dry land and wet land areas.
  • the inventive compounds are effective in controlling the above-said plants when applied to the foliage thereof or to the soil or water containing seeds or other propagating organs thereof such as stolons, tubers or rhizomes, at rates of from about 0.01 kg/ha to 4 kg/ha and preferably from about 0.01 kg/ha to 1 kg/ha.
  • the compounds of this invention are selective in the presence of soybeans and/or cereal crops such as corn, wheat and rice when applied preemergence or postemergence.
  • the compounds of formula I may be used for the selective control of undesirable plant species in transplanted rice culture by applying a herbicidally effective amount of a formula I compound to the soil or water containing seeds or other propagating organs of said undesirable plant species after the rice has been transplanted.
  • Those compounds of formula I which are especially useful for the selective control of undesirable plant species in the presence of corn include l-methyl-3-[3-(3-thienyl)-1,2-benzisothiazol-5-yl]-6-(trifluorome hyl)uracil;
  • Those compounds of formula I which are particularly useful for the selective control of undesirable plant species in the presence of wheat include l-methyl-3- [3-( 3-thienyl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-thienyl) -1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 3-methyl-2-thienyl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 5-methyl-2-thienyl) -1 ,2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil;
  • Formula I compounds of this invention which are particularly useful for the selective control of undesirable plant species in the presence of soybeans include l-methyl-3-[3-(3-thienyl)-1,2-benzisothiazol-5-yl]-6-(trifluoro- methyl)uracil;
  • Formula I compounds of this invention which are particularly useful for the selective control of undesirable plant species in the presence of transplanted rice include l-methyl-3-[ 3-( 5-methyl-2-thienyl) -1,2-benzisothiazol-5-yl] -
  • Formula I compounds of this invention which are particularly useful for total vegetation control include
  • While the compounds of this invention are effective for controlling undesirable plant species when employed alone, they may also be used in combination with or in conjunction with one or more other biological chemicals, including herbicides.
  • the compounds of this invention may be applied to the foliage of undesirable plant species or to the soil or water containing seeds or other propagating organs thereof in the form of a solid or liquid herbicidal composition, comprising a herbicidally effective amount of the desired compound dispersed or dissolved in an agronomically acceptable, inert solid or liquid carrier.
  • the compositions may be applied as preemergence or postemergence treatments .
  • the formula I compounds of the present invention may be formulated as emulsifiable concentrates, wettable powders, granular formulations, suspension concentrates, flowable concentrates and the like.
  • Q 36 and Q may be prepared from 5-aminobenzisothiazoles and 5-aminobenziso- xazoles of Formula II
  • Formula I compounds wherein Q is Q 8 may be prepared by reacting an amine of formula II with a substituted tetrahydrofuran of formula III as shown below in Flow Diagram I.
  • Formula I compounds wherein Q is Q 4 may be prepared from formula I compounds wherein Q is Q 8 using essentially the same procedures used to prepare formula I compounds wherein Q is Q 3 from formula I compounds wherein Q is Q 7 .
  • Compounds of formula I wherein ⁇ > is Q i5 may be prepared by reacting an amine of formula II with a substituted tetrahydrofuran of formula III to form an acid-amide of formula IV, and dehydrating the acid-amide with a dehydrating agent such as 1,3-dicyclohexyl- carbodiimide.
  • a dehydrating agent such as 1,3-dicyclohexyl- carbodiimide.
  • Formula I compounds wherein Q is Q 2i may be prepared from formula I compounds wherein Q is Q 8 using essentially the same procedure used to prepare formula I compounds wherein Q is Q 20 from formula I compounds wherein Q is Q 7 .
  • Compounds of formula I wherein Q is Q 23 may be prepared by converting an amine of formula II to its corresponding isocyanate or isothiocyanate of formula V using standard methods such as phosgene or thiophosgene in an inert solvent or palladium chloride and carbon monoxide, reacting the formula V compound with a substituted hydrazine of formula VI to form an intermediate compound of formula VII, and reacting the formula VII compound with an ester of formula VIII.
  • the reaction scheme is shown in Flow Diagram III. FLOW DIAGRAM III
  • Formula I compounds wherein Q is Q 26 may be prepared by reacting an amine of formula II with a ⁇ -aminoacrylic acid chloride of formula IX to form an intermediate compound of formula X, and reacting the intermediate compound with an acid chloride of formula XI.
  • the reaction scheme is shown in Flow Diagram IV. FLOW DIAGRAM IV
  • Formula I compounds wherein Q is Q 28 may be prepared by reacting an amine of formula II with an unsaturated lactone of formula XIV as shown below in Flow Diagram VI. FLOW DIAGRAM VI
  • formula I compounds wherein Q is 29 may be prepared by reacting an amine of formula II with a lactone of formula XV.
  • the reaction scheme is shown in Flow Diagram VII.
  • Compounds of formula I wherein Q is Q 30 may be prepared, as shown in Flow Diagram VIII, by reacting an isocyanate or isothiocyanate of formula V with an unsaturated lactone of formula XVI at an elevated temperature.
  • formula I compounds wherein Q is Q 3l may be prepared by reacting an isocyanate or isothiocyanate of formula V with a lactone of formula XVII at an elevated temperature.
  • the reaction scheme is shown in Flow Diagram IX.
  • Formula I compounds wherein Q is Q 34 may be prepared, as shown in Flow Diagram X, by reacting an isocyanate or isothiocyanate of formula V with a substituted hydrazine of formula XVIII to form an intermediate compound of formula XIX, and reacting the formula XIX compound with an acetal of formula XX at an elevated temperature .
  • Formula I compounds wherein Q is Q 37 may be prepared, as shown in Flow Diagram XI, by reacting an isocyanate or isothiocyanate of formula V with an amine of formula XXI to form an intermediate of formula XXII, and reacting the intermediate with an ⁇ -haloketone of formula XXIII.
  • Formula I compounds wherein Q is Q 39 may be prepared by reacting an amine of formula II with a chloride compound of formula XXV to form an intermediate compound of formula XXVI, and reacting the intermediate compound with hydrogen sulfide, hydrogen chloride and sodium periodate.
  • the reaction scheme is shown in Flow Diagram XIII.
  • Compounds of formula I wherein Q is Q 33 may be prepared, as shown in Flow Diagram XV, by acylating a compound of formula XXXI with acetyl chloride and aluminum chloride to form an acetophenone of formula XXXII, reacting the acetophenone compound with an ester of formula XXXIII in the presence of a base to form a diketone compound of formula XXXIV, and reacting the formula XXXIV compound with a substituted hydrazine of formula VI.
  • Another preferred method for the preparation of intermediates XL is shown in Flow Diagram XVIII, by reaction of an amine of formula II with a urea of Formula XLI in the presence of an acid or base, wherein R 82 and R 83 are each independently C ⁇ -Cg-alkyl or R ⁇ and R 83 may be taken together with the atom to which they are attached to form a 5- or 6-membered ring optionally containing one oxygen atom.
  • 5-Aminobenzisothiazole and 5-aminobenzisoxazole compounds of formula II can be prepared by reduction of 5-nitro intermediates of formula XLIV as shown in Flow Diagram XX using standard conditions such as iron in acetic acid, stannous chloride and hydrochloric acid, or dithionite.
  • the 5-nitro intermediates XLIV can be prepared from ketones of formula XLIII by methods described in US 5,484,763, also shown in Flow Diagram XX.
  • Ketones of formula XLIII where Y is Yx may be prepared by reaction of organolithium reagents XLIX with zinc chloride followed by coupling with acid chloride LI in the presence of a palladium catalyst as shown in Flow Diagram XXII. Under essentially the same conditions, ketones of formula XLIII where Y is Y are prepared from organometallic reagents L. Organometallic reagents XLIX and L may be prepared by standard methods such as direct deprotonation of the heterocycle Y, or by halogen-metal exchange with a halogenated heterocycle Y.
  • Ketones of formula XLIII wherein Yx is a substituted 2-furanyl radical may additionaly be prepared by reaction of organotin reagent LII with acid chloride LI as shown in Flow Diagram XXIII .
  • Ketones of formula XLIV wherein Y is a substituted 2- or 3-thienyl radical may additionally be prepared by reaction of thiophene LIV with acid chloride LI, in the presence of a Lewis acid such as aluminum chloride as shown in Flow Diagram XXIV.
  • a Lewis acid such as aluminum chloride as shown in Flow Diagram XXIV.
  • ketones of formula XLIV wherein Yx is a substituted 2-thienyl radical may be prepared by treatment of acid LIU with thiophene LIV in the presence of phosphorous pentoxide.
  • Ketones of formula XLIV wherein Y is Y 3 may be prepared by treatment of nitrile LV with lithiated pyridine LVII followed by acid hydrolysis to afford intermediate ketone compound LVII, which is nitrated under standard conditions as depicted in Flow Diagram XXV.
  • Lithiated pyridine XLVIII may be prepared from the corresponding bromopyridine by treatment with n-butyllithium.
  • Ketones of formula XLIV wherein Y is Y 5 may be prepared by heating nitrile LVIII with bromopyrimidine LIX to afford intermediate LX, which on oxidation yields ketone LXI, which can be nitrated as depicted in Flow Diagram XXVI. FLOW DIAGRAM XXVI
  • nitro ketones of formula XLIV where where Y is Yx, Y , Y 3 and Y 5 may be converted into nitro intermediate XLIV and amino intermediate II by the methods shown in Flow Diagram XX.
  • Ketones of formula XLV wherein Y is Y may be prepared by reaction of nitrile LXII with organolithium reagent LXIV followed by hy- drolysis under acidic conditions as shown in Flow Diagram XXVII.
  • ketones XLV wherein Y is Y may be prepared by reaction of Grignard reagent LXIII with pyridylnitrile LXV folio- wed by hydrolysis under acidic conditions as shown in Flow Diagram XXVII.
  • ketones XLV wherein Y is Y 3 may be converted to 5-aminobenzisoxazoles and 5-aminobenzthiazoles wherein Y is Y 3 by the method outlined in Flow Diagram XXI.
  • Intermediate thioamide compound of formula LXVI can be prepared by standard methods such as treatment amide compound of formula LXX with Lawson's reagent or phosphorous pentasulf ide.
  • Formula LXX amides are prepared from acid LXVIII by treatment of its acid chloride derivative LXIX with ammonia as depicted in Flow Diagram XXIX.
  • Intermediate acid compounds of formula LXVIII may be prepared by bromination of methyl intermediate LXXI to afford a mixture of monobromo (LXXII) and dibromo (LXXIII) intermediate compounds, subsequent oxidation of this mixture with silver tetrafluorobo- rate to afford a mixture of alcohol LXXIV and aldehyde LXXV, and final oxidation of this mixture with potassium dichromate in the presence of acid as shown in Flow Diagram XXX. FLOW DIAGRAM XXX
  • Nitro intermediates XLIV and benzisothiazoles and benzisozaxoles II wherein Y is Y 6 may be prepared from 3-chloro intermediate compounds LXXVIII and LXXIX respectively by treatment with pyrazole LXXX in the presence of an organic base as shown in Flow Diagram XXXIII.
  • Nitro intermediate compounds LXXVIII are prepared from acid intermediate LIU by conversion to disulfide LXXXI by sequential treatment with base, sodium sulfide, and acid as depicted in Flow Diagram XXXIV.
  • Intermediate disulfide compound LXXXI is conver- ted to intermediate benxisothiazolone LXXXII by sequential treatment with thionyl chloride, bromine and ammonia, and this product then treated with phosphorous oxychloride in the presence of base.
  • LXXVIII Benzisothiazole and benzisozaxole intermediate compound LXxix is prepared as shown in Flow Diagram XXXV from nitro intermediate LXXVIII by reduction to amino intermediate LXXXIII under standard conditions such as iron in the presence of acid, followed by elaboration of the amino functionality to Q groups as described in u. S. 5,484,763, U. S. 5,523,278 and Flow Diagrams I-XIX. FLOW DIAGRAM XXXV
  • Diketone LXXXVII is treated with hydrazine to afford a mixture of pyrazole regioiso-
  • FLOW DIAGRAM XLI FLOW DIAGRAM XLI
  • Acid chloride CIV may be prepared as outlined in Flow Diagram XLII.
  • Treatment of thiophenol CIV with oxalyl chloride followed by aluminum chloride affords thiodione CV, which on treatment with ammonium hydroxide and hydrogen peroxide yields amide CVI.
  • Basic hydrolysis of amide CVI affords acid CVII, which is nitrated under standard conditions to afford acid CVIII.
  • Treatment of acid CVIII with thionyl chloride affords acid chloride CIV.
  • ketoester CXII is prepared from chloro intermediate LXXVIII by treatment with cyanoacetic ester in the presence of base to afford intermediate cyanoester CXV which on treatment with acetyl chloride affords nitro ester CXVI .
  • Reduction of nitro ester CVIII with iron in acetic acid affords amino ester CXVII which can be elaborated into an intermediate ester of formula CXVIII by the methods described in Flow Diagrams I-XIX.
  • Oxidation of ester CXVIII with selenium dioxide affords ketoester CXIII as shown in Flow Diagram XLV. FLOW DIAGRAM XLVI
  • compounds I wherein Y is Y 24 and both B and B are oxygen can be prepared by treatment of dibromo intermediate LXXIII with diol CXXXVI in the presence of a silver salt such as silver trifluoromethanesulfonate as shown in Flow Diagram LIV.
  • Compounds I wherein Y is Y 29 and Y 30 can be prepared by treatment of ketone CXXXV with hydroxy acids CXXXIX and CXL, respectively, under acidic conditions with azeotropic removal of water as shown in Flow Diagram LVI .
  • Y is Y 3 ⁇ and Y 33 can be prepared from keto ester CXLI by conversion to diol CXLIII by reduction for the case wherein R ⁇ 5 ( X 6) is hydrogen, or by reaction with organolithium reagent CXLII followed by reduction for the case wherein RXS ( 6 ) is not hydrogen, and subsequent reaction of diol intermediate CXLIII with aldehyde CXLIV in the presence of acid, with azeotropic removal of water or by reaction with phosgene or thiophosgene as shown in Flow Diagram LVII.
  • Keto ester CXXXII can be prepared from chloro intermediate LXXVIII using the procedure described in Flow Diagram XLV.
  • Compound XLIV wherein Y is Y 32 and Y 34 can be prepared from chloro intermediate LXXVIII by treatment with a dialkyl malonate in the presence of base to form diester CXLV, which can be alkylated with alkylating agent CXLVI to produce diester CXLVII.
  • Diester CXLVII can be reduced to diol CXLVIII, which is treaed with aldehyde CXLIV in the presence of acid with azeotropic removal of water, or with phosgene or thiophosgene as depicted in Flow Diagram LVIII .
  • Compounds I wherein Y is Y 35 may be prepared reaction of the anion of ester CXVIII with aldehyde CXLIV to generate diol intermediate CXLIX, which is treated with aldehyde CL in the presence of acid with azeotropic removal of water as depicted in Flow Diagram LIX.
  • Compounds I wherein Y is Y 37 may be prepared by conversion of ester CXVIII to acid chloride CLII by sequential treatment with aqueous sodium hydroxide, N-chlorosuccinimide or N-bromosuccini - mide, and oxalyl chloride. Treatment of acid chloride CLII with reagent CLIII in the presence of base affords compound I wherein Y is Y 37 . FLOW DIAGRAM LXI
  • Compounds I wherein Y is Y 3 8 may be prepared by conversion of diol CXLIII to halo intermediate CLIV and subsequent treatment with reagent CLV in the presence of a silver salt as depicted in Flow Diagram LXII . FLOW DIAGRAM LXII
  • the present invention also relates to intermediate compounds having the structural formula XLIV
  • Preferred intermediate compounds of formula XLIV are those whe rein Y is selected from
  • Ri5' R-18 R 2 0 and R ⁇ are each independently hydrogen, C ⁇ -C 8 alkyl, C ⁇ -C 8 haloalkyl, C ⁇ -C 8 alkoxy, C ⁇ -C 8 thioalkyl, halogen, nitro, cyano, hydroxy, C 2 -C6 alkenyl, C 3 -C 6 alkynyl, C 2 -C 6 haloalkenyl, C 3 -C 8 cycloalkyl or R 20 and the carbon on Y to which R 0 is attached may form an exocyclic double bond or when R 2 o and R ⁇ are attached to the same carbon of Y 5 , R o, R 21 and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring;
  • R 5 and R ⁇ 6 are attached to separate adjacent carbons, as in Y 24 , they may form a six-membered heterocyclic or carbo- cyclic ring fused to the Y-ring;
  • R ⁇ 7 is hydrogen, C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 alkynyl, C(0)R 25 , or (subst. ) benzyl ;
  • R 75/ 76 R 80 and R 85 are each independently hydrogen, OH, C ⁇ -C 8 alkyl, C ⁇ -C alkoxy,
  • R 79 are each independently hy ⁇ drogen, C ⁇ -C 8 alkyl, C ⁇ -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 halocycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 haloalkenyl, C 5 -C 8 cycloalkenyl, Cs-C 8 halocycloalkenyl, C 3 -C 8 alkynyl, C 3 -C 8 haloalkynyl, (subst.
  • R 27 and R 28 are each independently hydrogen
  • C(0)ON CR 73 R 74 , cyano, (subst. )phenyl or C(0)NHOR 75 ; phenyl optionally substituted with one to three halogens, one to three C ⁇ -C 6 alkyl groups, one to three C ⁇ -C 6 alkoxy groups, one to three C ⁇ -C 6 haloalkyl groups, one to three C ⁇ -C 6 haloalkoxy groups, one cyano, one nitro, one NR 76 R 77 , one C(0)R 8 or one C0 2 R 79 .
  • R 30 is OH, C ⁇ -C 8 alkyl, C 3 -C 8 cycloalkyl, C ⁇ -C 8 haloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 haloalkenyl, C 3 -C 8 alkynyl, (subst. )benzyl, (subst.) phenyl, or NR 8 oR 8 ⁇ ;
  • B and Bx are each independently oxygen, sulfur or NR ⁇ ;
  • X 2 and X 3 are each independently 0 or S; and all optical isomers and diastereomers thereof.
  • X is hydrogen or halogen,- Xx is hydrogen
  • Z is sulfur of oxygen; Y is selected from Yx, Y 2 , Y 3 , Y 4 , Y 5 . e Y ⁇ o> Yn> Yi4» Yi5.
  • Ri5# i8» 20' and R ⁇ are each independently hydrogen, C ⁇ -C 3 alkyl, C ⁇ -C 3 haloalkyl, C ⁇ -C 3 alkoxy, halogen, hydroxy or when R 2 o and R 2 ⁇ are attached to the same carbon of Y 25 an epoxide ring is formed;
  • R ⁇ 6 is hydrogen, halogen, C ⁇ -C 3 alkyl optionally substituted with C(0)R 22 , C0 2 R 23 , X 2 R 24 or S(0) m alkyl; phenyl; C -C 3 haloalkyl, C(0)R 25 , C0 2 R 26 , X 3 R 2 7/ C 3 -C 8 cycloalkyl, N(R 29 )SO 2 R 30 or C 2 -C alkenyl;
  • R ⁇ 7 is hydrogen, C ⁇ -C 3 alkyl, C 2 -C 4 alkenyl or C(0)R 25 ;
  • Ri9 R29 and R 8 o are each independently hydrogen or C ⁇ -C 3 alkyl;
  • 22 25 and R 8 ⁇ are each independently hydrogen, C ⁇ -C 3 alkyl, benzyl or (subst) phenyl ,-
  • R 23 , R 26 and R 3 ⁇ are each independently hydrogen, C ⁇ -C 3 alkyl, C 2 -C 4 alkenyl, or C 3 -C 6 alkynyl;
  • R 24 and R 27 are each independently hydrogen or C ⁇ -C 3 alkyl optionally substituted with one C0 2 R 3 ⁇ group or one C ⁇ -C 3 alkoxy group;
  • R 30 C ⁇ -C 3 alkyl, C 3 -C 5 cycloalkyl, C ⁇ -C 3 haloalkyl, C 2 -C 4 alkenyl (subst.) benzyl, (
  • i 5 i 8 20 and R21 are each independently hydrogen, C ⁇ -C 3 alkyl, C ⁇ -C 3 haloalkyl, C ⁇ -C 3 alkoxy;
  • R ⁇ 6 is hydrogen, halogen, C ⁇ -C 8 alkyl optionally substituted with X2 24; C ⁇ -C 3 haloalkyl , phenyl or C2-C4 alkenyl;
  • R17 IS hydrogen, methyl or C(0)R 2 s
  • R 19 is hydrogen or C ⁇ -C 3 alkyl
  • R24 is hydrogen or C ⁇ -C 3 alkyl; 25 is C ⁇ -C 3 alkyl or phenyl; X 2 is oxygen.
  • the present invention also relates to intermediate compounds ha- ving the structural formula II
  • Preferred intermediate compounds of formula II are those wherein Y is selected from
  • R20 and R 2 ⁇ are each independently hydrogen, C ⁇ -C 8 alkyl, C ⁇ -C 8 haloalkyl, C ⁇ -C 8 alkoxy, C ⁇ -C 8 thioalkyl, halogen, nitro, cyano, hydroxy, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, C 2 -C 6 haloalkenyl, C 3 -C 8 cycloalkyl or R 2 o and the carbon on Y to which R 2 0 is attached may form an exocyclic double bond or when R 20 and R 2X are attached to the same carbon of Y 2 5, 20 R 21 and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring;
  • R ⁇ 6 is hydrogen, halogen, C ⁇ -C 8 alkyl optionally substituted with C(0)R 22 , C0 2 R 2 3- 2 24 S(0) m alkyl, NR 86 R 87 , C ⁇ -C 8 haloalkyl, C(0)R 2 5, C0 2 R 2 6, 3 27, C 3 -C 8 cycloalkyl, N(R 29 )SO2R30 or (subst.) phenyl ,-
  • R 5 and R ⁇ 6 are attached to separate adjacent carbons, as in Y 24 , they may form a six-membered heterocyclic or carbo- cyclic ring fused to the Y-ring;
  • R ⁇ 7 is hydrogen, C ⁇ -C 8 alkyl, C 2 ⁇ C 8 alkenyl, C 3 -C 6 alkynyl, C(0)R 2 5, or (subst .) benzyl;
  • 76 R ⁇ O and R 85 are each independently hydrogen, OH, C ⁇ -C 8 alkyl, C ⁇ -C 4 alkoxy, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 3 -C 6 alkynyl, (subst.) benzyl or (subst.) phenyl;
  • R 23 , R 2 6 R3 1 R40 R49' R58' ⁇ 7 and R 79 are each independently hydrogen, C ⁇ -C 8 alkyl, C ⁇ -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C -C 8 halocycloalkyl, C 2 ⁇ C 8 alkenyl, C 2 -C 8 haloalkenyl, C 5 -C 8 cycloalkenyl, C 5 -C 8 halocycloalkenyl, C 3 -C 8 alkyn
  • R24. 27» and R 28 are each independently hydrogen,
  • C0 2 R 5 8, C(O)R 59 ,C(OR 60 ) 2 , C(SR 6 ⁇ ) 2 / C(0)NR 62 R 6 3 C(0)ON CR 64 R 65 , cyano, (subst. ) phenyl or C(0)NHOR 66 .
  • C 3 -C 8 alkynyl optionally substituted with one C -C ⁇ alkoxy group, C0 2 R 6 7/ C (0)R 68 ,C (OR 69 ) 2 , C(SR 70 ) 2 / C(0)NR 7 ⁇ R 72 , C(0)ON CR 73 R 74 , cyano, (subst. ) phenyl or C(0)NHOR 75 ;
  • phenyl optionally substituted with one to three halogens, one to three C ⁇ -C 6 alkyl groups, one to three C ⁇ -C 6 alkoxy groups, one to three C ⁇ -C 6 haloalkyl groups, one to three C ⁇ -C 6 halo- alkoxy groups, one cyano, one nitro, one NR 76 R 7 , one C(0)R 8 or one C0 2 R7 9;
  • R 30 is OH, C ⁇ -C 8 alkyl, C 3 -C 8 cycloalkyl, C ⁇ -C 8 haloalkyl, C 2 -C 8 alkenyl, C 2 ⁇ C 8 haloalkenyl, C 3 -C 8 alkynyl, (subst. ) benzyl, (subst.) phenyl, or NR 8 oR 8 ⁇ ;
  • B and Bx are each independently oxygen, sulfur or NR ⁇ 7 ;
  • X and X 3 are each independently 0 or S; and all optical isomers and diastereomers- thereof.
  • More preferred formula II intermediate compounds of this invention are those wherein
  • Y is selected from Yx, Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 10 , Yxx, Y 14 , Y ⁇ 5 Yi6.
  • i5 R 18 R 2 0 and R 2X are each independently hydrogen, C ⁇ -C 3 alkyl,
  • R 2 o and R 2X are attached to the same carbon of Y 25 an epoxide ring is formed;
  • R ⁇ 6 is hydrogen, halogen, C ⁇ -C 3 alkyl optionally substituted with C(0)R 22 , C0 2 R 2 3 X 2 R 24 / or S(0) m alkyl; phenyl; C -C 3 haloalkyl, C(0)R 25 , C0 2 26# X3R 2 7 C 3 -C 8 cycloalkyl,
  • R ⁇ 7 is hydrogen, C ⁇ -C 3 alkyl, C 2 -C 4 alkenyl or C(0)R 25 ,- R 23 , R 26 and R 3 ⁇ are each independently hydrogen, C ⁇ -C 3 alkyl,
  • R 22 R 5 and Rsi are each independently hydrogen, C ⁇ -C 3 alkyl, benzyl or (subst) phenyl;
  • R 24 and R 27 are each independently hydrogen or C ⁇ -C 3 alkyl optio - nally substituted with one C0 2 R 3 ⁇ group or one C ⁇ -C alkoxy group;
  • R ⁇ 9 , R 29 and R ⁇ o are each independently hydrogen or C ⁇ -C alkyl;
  • R 30 C ⁇ -C 3 alkyl, C 3 -C 5 cycloalkyl, C ⁇ -C 3 haloalkyl, C 2 -C 4 alkenyl
  • R l 5 i8 R 20 and R 2X are each independently hydrogen, C ⁇ -C 3 alkyl
  • R ⁇ 6 is hydrogen, halogen, C ⁇ -C 8 alkyl optionally substituted with X 2 R 24 ; C ⁇ -C 3 haloalkyl, phenyl or C 2 -C 4 alkenyl;
  • R ⁇ is hydrogen, methyl or C(0)R 2 5;
  • R 24 is hydrogen or C ⁇ -C alkyl;
  • R 25 is C ⁇ -C alkyl or phenyl;
  • R ⁇ 9 is hydrogen or C ⁇ -C 3 alkyl;
  • X 2 is oxygen .
  • the present invention also relates to intermediate compounds of having the structural formula XL
  • Preferred compounds of formula XL are those where Y is selected from
  • Ri8 R20 and R are each independently hydrogen, C ⁇ -C 8 alkyl, C ⁇ -C 8 haloalkyl, C ⁇ -C 8 alkoxy, C ⁇ -C 8 thioalkyl, halogen, nitro, cyano, hydroxy, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, C 2 -C 6 haloalkenyl, C 3 -C 8 cycloalkyl or R 20 and the carbon on Y to which R 2 o is attached may form an exocyclic double bond or when R 2 o and R2X are attached to the same carbon of Y 25 , 20 R 2 ⁇ and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring;
  • R ⁇ 6 is hydrogen, halogen, C ⁇ -C 8 alkyl optionally substituted with C(0)R 22 , C0 2 R 2 3 X 2 24 S(0) m alkyl, NR 86 R 87 , C ⁇ -C 8 haloalkyl, C(0)R 25 .
  • C0 2 R 2 6, X3 27 CH CHR 28 , C 3 -C 8 cycloalkyl, N(R 29 )SO 2 R30 or (subst.) phenyl ;
  • R ⁇ 5 and R ⁇ 6 are attached to separate adjacent carbons, as in Y 24 , they may form a six-membered heterocyclic or carbocyclic ring fused to the Y-ring;
  • R ⁇ 7 is hydrogen, C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 alkynyl, C(0)R 25 , or (subst. ) benzyl; Rl9# 29 R 33' R34 R 35 37 38 R39 R 42/ R 43' R 44/ R46 R47 48 R50 R51 R52 R53/ R55 R56/ 57» R60 R ⁇ l/ R62 R64 ⁇ 5 / R ⁇ 6 / 69 R70 R71 R?3» R74 R75» R76/ R ⁇ o and R 8 5 are each independently hydrogen, OH, C ⁇ -C 8 alkyl, C ⁇ -C 4 alkoxy, C 3 -C 8 cyclo- alkyl, C 2 -C 8 alkenyl, C 3 -C 6 alkynyl, (subst.) benzyl or (subst.) phenyl; R 23 R 26» R31 R40 R 49# R58 67# and R 9
  • R 24 , R 2 7, and R 2 8 are each independently hydrogen,
  • C(0)NR4 4 R 45 , C(0)ON CR 46 R 7 , cyano, (subst .) phenyl or C(0)NHOR 48 ; C 3 -C 8 cycloalkyl optionally substituted with one C ⁇ -C 6 alkyl group, one to three halogens, one C ⁇ -C 6 alkoxy group,
  • phenyl optionally substituted with one to three halogens, one to three C ⁇ -C 6 alkyl groups, one to three C ⁇ -C 6 alkoxy groups, one to three C ⁇ -C 6 haloalkyl groups, one to three C ⁇ -C 6 halo- alkoxy groups, one cyano, one nitro, one NR 76 R 77 , one C(0)R 8 or one C0 2 R 9;
  • R 30 is OH, C -C 8 alkyl, C 3 -C 8 cycloalkyl, C ⁇ -C 8 haloalkyl, C 2 -C 8 alkenyl, C 2 ⁇ C 8 haloalkenyl, C 3 -C 8 alkynyl, (subst. ) benzyl, (subst.) phenyl, or NR 80 R 8 ⁇ ;
  • B and Bx are each independently oxygen, sulfur or NR ⁇ ;
  • X 2 and X 3 are each independently O or S;
  • R is C ⁇ -C 3 haloalkyl
  • X is hydrogen or halogen
  • x is hydrogen
  • Z is sulfur
  • Y is selected from Y lf Y 2 , Y 3 Y 4 , ⁇ s# Ye, Y ⁇ o# Yii. Yi4.
  • R20 and R ⁇ are each independently hydrogen, C ⁇ -C 8 alkyl, C ⁇ -C 8 haloalkyl, C ⁇ -C 8 alkoxy, C ⁇ -C 8 thioalkyl, halogen, nitro, cyano, hydroxy, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, C 2 -C 6 haloalkenyl, C 3 -C 8 cycloalkyl or R o and the carbon on Y to which R 2 o is attached may form an exocyclic double bond or when R 20 and R 2 ⁇ are attached to the same carbon of Y25, R20/ R21 and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring; R ⁇ 6 is hydrogen, halogen, C ⁇ -C 8 alkyl optionally substituted with C(0)R 22 , C0 2 R 2 3, 2 4 S(0) m alkyl, NR 86 R 87 , C
  • R ⁇ 5 and R ⁇ 6 are attached to separate adjacent carbons, as in Y 24 , they may form a six-membered heterocyclic or carbocyclic ring fused to the Y-ring;
  • R ⁇ 7 is hydrogen, C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 6 alkynyl, C(0)R 25 , or (subst. ) benzyl ; l9 9' 33 R34» R35/ 37 38 R39 42 43' R44' 46/ 47 8 R50' 51 R52 R 53# R55/ R56 R 57/ R60 ⁇ l' R 62/ R 64/ R 65
  • R 73 R74/ 75 R76/ ⁇ o/ and R 85 are each independently hydrogen, OH, C ⁇ -C 8 alkyl, C ⁇ -C 4 alkoxy, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 3 -C 6 alkynyl, (subst.) benzyl or (subst.) phenyl;
  • R 23' R 6 R 3i R40/ R 9 R58, R 67 and R 9 are each independently hydrogen, C ⁇ -C 8 alkyl, C ⁇ -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 halocycloalkyl, C 2 ⁇ C 8 alkenyl, C 2 -Cs haloalkenyl, C 5 -C 8 cycloalkenyl, Cs-C 8 halocycloalkenyl, C 3 -Cs al
  • R 24 , R 7 , and R 28 are each independently hydrogen,
  • c 2 -c ⁇ o alkenyl optionally substituted with one C ⁇ -C 6 alkyl group, one to three halogens, one C ⁇ -C 6 alkoxy group, C0 2 R 40 , C(0)R 4 ⁇ ,C(OR 42 )2, C(SR 43 ) 2 , C(0) R 44 R45, C(0)ON CR 6 R 47 , cyano, (subst. ) phenyl or C (0)NHOR 48 ;
  • C 3 -C 8 alkynyl optionally substituted with one C ⁇ -C 6 alkoxy group, C0 2 R 6 7, C (0)R 68 ,C (OR 69 ) 2 .
  • C(SR 70 ) 2* C(0)NR 71 R 72 , C(0)0N CR 73 R 7 , cyano, (subst. ) phenyl or C(0)NHOR 75 ;
  • phenyl optionally substituted with one to three halogens, one to three C ⁇ -C 6 alkyl groups, one to three C -C ⁇ alkoxy groups, one to three C ⁇ -C 6 haloalkyl groups, one to three C-C ⁇ halo- alkoxy groups, one cyano, one nitro, one NR 6 R 77 , one C(0)R 8 or one C0 2 R 9;
  • R 3 o is OH, C ⁇ -C 8 alkyl, C 3 -C 8 cycloalkyl, C ⁇ -C 8 haloalkyl, C 2 -C 8 alkenyl, C 2 ⁇ C 8 haloalkenyl, C 3 -C 8 alkynyl, (subst. )benzyl, (subst.) phenyl, or NR S QRS I ;
  • B and Bx are each independently oxygen, sulfur or NR ⁇ ;
  • X 2 and X 3 are each independently O or S; and all optical isomers and diastereomers thereof.
  • Ri8 R 0 and R 2 X are each independently hydrogen, C ⁇ -C 3 alkyl , C ⁇ -C 3 haloalkyl , C ⁇ -C 3 alkoxy;
  • R ⁇ 6 is hydrogen, halogen, C ⁇ -C 8 alkyl optionally substituted with X 2 R 24 C ⁇ -C 3 haloalkyl , phenyl or C 2 -C 4 alkenyl ;
  • R ⁇ 7 is hydrogen, methyl or C (0) R 5 ;
  • R24 is hydrogen or C ⁇ -C 3 alkyl
  • R 25 is C ⁇ -C 3 alkyl or phenyl ;
  • R ⁇ 9 is hydrogen or C ⁇ -C 3 alkyl ; X is oxygen.
  • the present invention also relates to intermediate compounds of having the structural formula CXIII
  • Preferred compounds of formula CXIII are those wherein
  • Q is Q 7 or Q24
  • R is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl or NH 2 ;
  • R 2 is C ⁇ -C 6 alkyl or C ⁇ -C 6 haloalkyl
  • R 3 is hydrogen
  • Q is Q 24 ;
  • R is C ⁇ -C 3 alkyl
  • R 2 is C ⁇ -C 3 haloalkyl
  • Z is sulfur
  • X is hydrogen or halogen
  • Z is sulfur; X 2 is oxygen.
  • N-methyl- pyrrole 40.6 g, 0.500 mol
  • Zinc chloride 0.5 M in tetrahydrofuran, 500 ml, 0.25 mol
  • the resultant mixture is allowed to warm to 0°C and stirred one hour at 0°C.
  • the acidic aqueous layers are combined, stirred one hour at reflux and cooled to room temeperature.
  • the mixture is basified with 5% aqueous sodium hydroxide and extracted with diethyl ether.
  • the organic layer is concentrated in vacuo and the residue is chromatographed on silica gel to provide the title compound as a yellow oil (22.3 g, 68.0%) which is identified by NMR spectral analysis.
  • Ammonia (45 g, 2,642 mmol) is bubbled into methanol at -40 °C in a steel bomb. Sulfur (30.5 g, 95.0 mmol) and 2' -chloro-5' -nitroacetophenone (19 g, 95.0 mmol) are then added. The bomb is sealed and heated at about 90 °C overnight. After cooling, the reaction mixture is removed from the bomb and concentrated in vacuo to obtain a residue. The residue is diluted with methylene chloride. passed through a plug of silica gel and concentrated in vacuo to give the title product as an orange solid (12.0 g) which is identified by NMR spectral analyses .
  • the resultant filtrate is poured into a methylene chloride and water mixture.
  • the organic phase is separated, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a 2:3 mixture of the title products.
  • a solution of potassium dichromate (10.0 g) in 1.5 M sulfuric acid (200 mL) is cooled to 0°C, treated dropwise with a solution of a 2:3 mixture of 3- [3- (hydromethyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) -2, 4 (IH, 3H) -pyrimidinedione and 5- [3 , 6-dihydro-3-methyl-2 , 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxaldehyde (12.0 g) in acetic acid, stirred at room temperature for 2 hours, and diluted with water.
  • the resultant mixture is stirred 7.5 hours at ambient temperature, diluted with diethyl ether, washed with IM aqueous hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with hexanes-ethyl acetate to afford the title compound as a solid (2.12 g, 86.2%, mp 120°C) which is identified by NMR spec- tral analysis.

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Abstract

There are provided 3-heterocyclic substituted benzisothiazole and benzisoxazole compounds having structural formula (I) wherein the variables have the meanings given in the description. Further provided are compositions and methods comprising those compounds for the control of undesirable plant species.

Description

HERBICIDAL 3-HETEROCYCLIC SUBTITUTED BENZISOTHIAZOLE AND BENZISOXAZOLE COMPOUNDS
BACKGROUND OF THE INVENTION
Weeds cause tremendous global economic losses by reducing crop yields and lowering crop quality. Worldwide, agronomic crops must compete with hundreds of weed species.
In spite of the commercial herbicides available today, damage to crops caused by weeds still occurs. Accordingly, there is ongoing research to create more effective and/or more selective herbicidal agents.
Certain benzisoxazole and benzisothiazole herbicidal agents are described in U.S. Patent Nos. 5,484,763 and 5,523,278. Those patents generically disclose benzisoxazole and benzisothiazole compounds that are substituted in the 3-position with a variety of substituents, none of which are heterocycles . In addition, those patents do not disclose that their compounds are useful for the selective control of weeds in the presence of crops such as corn, soybeans, wheat and transplanted rice.
WO 99/14216 also discloses benzisothiazol-substituted uracil compounds and their use as herbicides.
Surprisingly, it has now been found that benzisoxazole and benzisothiazole compounds in which the 3-position is substituted by an optionally substituted heterocycle are more effective and/or more selective herbicidal agents than those disclosed in these patents .
Therefore it is an object of the present invention to provide 3-heterocyclic substituted benzisoxazole and benzisothiazole compounds which are highly effective for the control of undesirable plant species.
It is also an object of the present invention to provide inter- mediate compounds useful in the manufacture of said compounds.
It is a further object of the present invention to provide methods for the selective control of undesirable plant species in the presence of crops. Those and other objects and features of the present invention will become more apparent from the detailed description thereof set forth below.
SUMMARY OF THE INVENTION
The present invention provides compounds of formula I
Figure imgf000003_0001
wherein Q is selected from
Figure imgf000003_0002
Q2 Q3 Q4
Figure imgf000003_0003
Q9 )10 oil ni2
Figure imgf000004_0001
Figure imgf000004_0002
Q29 Q30 Q31 Q32
Figure imgf000005_0001
Q37 Q38 Q39 Q40
R is halogen , Ci-Cβ-alkyl , Ci-Cβ-haloalkyl , C3-C7-cycloalkyl , C2-C6-alkenyl , C2-C6-haloalkenyl , C3-C6-alkynyl , cyano , benzyl , hydroxyl , amino , C -C6-cyanoalkyl;
Ri is hydrogen, halogen, Ci-Cβ-alkyl, Cι-C6-haloalkyl, C3-C7- cycloalkyl, C2-C6-alkenyl, C2-Cg-haloalkenyl, C3-C6~al- kynyl, cyano, benzyl, hydroxyl, amino, C2-C6-cyanoalkyl or R and Rl, together with the other atoms to which they are attached, form a four to seven-membered ring optionally interrupted by oxygen, sulfur or nitrogen and optionally substituted with one to three methyl groups or one or more halogen atoms;
R2 and R3 are, independently of one another, hydrogen, halogen,
Ci-Cβ-alkyl, Ci-Cε-haloalkyl, C3-C7-cycloalkyl, C2-C6-al- kenyl, C2-C6-haloalkenyl, C3-C6-alkynyl, OR8, S(0)m-R9, NRIORU or
R2 and R3, together with the atoms to which they are attached, form a four to seven-membered saturated or unsaturated ring optionally interupted by oxygen, sulfur or nitrogen and optionally substituted with one to three methyl groups or one or more halogen atoms;
R4, R6 and R7 are each independently hydrogen, halogen or C÷L-Ce-alkyl;
R5 is hydrogen, halogen, Ci-Cβ-alkyl, Ci-Cβ-haloalkyl, C3-C7- cycloalkyl, C3-C6-alkenyl, C2-C6-haloalkenyl, C3-Cg-al- kynyl, 0Ri2 or SRX3; R8, R9, R12, R3 and R14 are each independently of one another hydrogen, Cι-C4-alkyl, Cχ-C4-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C3-C6-alkynyl, C3-C-cycloalkyl, c 2 _c 6-cyanoalkyl, benzyl or optionally substituted phenyl;
R10 is hydrogen, Ci-Cβ-alkyl, Cχ-C6-haloalkyl, optionally substituted phenyl or optionally substituted benzyl;
RU is Cχ-C6-alkyl, C2-C6-alkenyl, C3-C6-alkynyl, C3-C7-cyclo- alkyl, Ci-Cβ-haloalkyl, benzyl, optionally substituted phenyl or S(0)n-Rl4;
n is an integer of 0, 1 or 2 ;
A, Ai and A2 are each independently oxygen or sulfur;
X is hydrogen, halogen or Cι-C4-alkyl;
χi is hydrogen, halogen, Cχ-C4-alkyl, Cι-C-haloalkyl, Cχ-C4-alkoxy or Cχ-C4-haloalkoxy;
V is hydroxyl, halogen, Cχ-C4-alkoxy or Cχ-C -alkylthio;
R88 is cyano, Cι-C-alkyl, Cι-C4-haloalkyl, Cχ-C4-alkoxy,
Cι-C4-haloalkoxy, Cι-C4-alkylthio, Cχ-C4-alkylsulfinyl, Cχ-C4-alkylsulfonyl or Cχ-C4-haloalkylsulfonyl;
R89 is hydrogen, cyano, halogen, Cχ-C4-alkyl or Cχ-C4-haloalkyl,
Y is an optionally substituted three to seven-membered hetero- cyclic ring containing carbon and one to four heteroato s selected from oxygen, sulfur and nitrogen;
Z is oxygen or S(0)m;
m is an integer of 0, 1 or 2;
and all optical isomers and diastereomers thereof.
Also provided are intermediate compounds useful in the preparation of the herbicidal compounds of formula I.
The present invention further provides herbicidal compositions, and methods. DETAILED DESCRIPTION OF THE INVENTION
It has been found that the 3-heterocyclic substituted benzisothiazole and benzisoxazole compounds of formula I demonstrate increased weed control and enhanced crop selectivity. The compounds of formula I are particularly useful for the selective control of undesirable plant species in the presence of cereal crops such as corn, wheat and rice and in the presence of leguminous crops such as soybeans .
Preferred compounds I of the invention are those, wherein
Q is Q7 or Q24;
R is Cχ-C6-alkyl, C2-C6-alkenyl, C3-C6-alkynyl or amino;
R2 is Cχ-C6-alkyl or Cχ-C6-haloalkyl; R3 is hydrogen;
Y is selected from
Figure imgf000007_0001
γ4 γ5 Y6
Figure imgf000007_0002
Y7 γ8 γ9
Figure imgf000007_0003
γl0 γll γl2
Figure imgf000008_0001
yl3 γl4 γl5
Figure imgf000008_0002
yl6 y" yl8
Figure imgf000008_0003
γl9 γ20 γ21
Figure imgf000008_0004
γ22 γ23 γ24
Figure imgf000008_0005
γ25 γ26 γ27
Figure imgf000009_0001
γ28 γ29 γ30
Figure imgf000009_0002
γ31 γ32 γ33
Figure imgf000009_0003
γ34 γ35 γ36
Figure imgf000009_0004
γ40, wherein
Ri5, Ri8, R20 and R i are each independently hydrogen, Cχ-C8-alkyl, Ci-Cβ-haloalkyl, Cχ-Ca-alkoxy, Cχ-C8-thioalkyl, halogen, nitro, cyano, hydroxy, C2-C6-alkenyl, C3-Cg-alkynyl, C -C6-haloalkenyl, C3-Cg-cycloalkyl or R20 and the carbon on Y to which R20 is attached may form an exocyclic double bond or when R20 and R21 are attached to the same carbon of Y25, R20, R2i and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring;
Ri6 is hydrogen, halogen, Cχ-C8-alkyl optionally substituted with C(0)R22, CO-OR23, X2R24, S(0)m-alkyl, NR86R87,
Cχ-C8-haloalkyl, C(0)R5, CO-OR26, X3R27, CH=CHR28, C3-C8-cycloalkyl, N(R29)-S02-R30, optionally substituted phenyl or when Ri5 and RX6 are attached to adjacent carbon atoms, they may be taken together with the atoms to which they are attached to form a six-membered ring;
Ri? is hydrogen, Cχ-C8-alkyl, C2-C8-alkenyl, C3-C6-alkynyl, C(0)R25 or optionally substituted benzyl;
Rl9, R29, R33, R34f R35, R37, R38, R39f R42 , R43, R44 R46, R47 f R48, R50, R51f R52, R53f R55 R56 R57 f R60f R61, R62 , R64, R65, R66, R69, R70, R71, R73, R74f R75f R76, R80f R85 and R86 are, independently of one another, hydrogen, hydroxy, Cχ-Cs-alkyl, Cχ-C4-alkoxy, C3-Cs-cycloalkyl, C2-C8-al- kenyl, C3-C6-alkynyl, optionally substituted phenyl or optionally substituted benzyl;
R23, R26, R3i, R40, R49, R58, R67 and R79 are, independently of one another, hydrogen, Cχ-Cs-alkyl, Cχ-Cs-haloalkyl, C3-Cs- cycloalkyl, C3-C8-halocycloalkyl, C2-C8-alkenyl, C2-Cs- haloalkenyl, Cs-Cs-cycloalkenyl, Cs-Cs-halocycloalkenyl, C3-C8-alkynyl, C3-Cs-haloalkynyl, optionally substituted phenyl, optionally substituted benzyl, furfuryl, pyridyl, thienyl, an alkali metal, alkaline earth metal, manganese, copper, zinc, cobalt, silver, nickel, ammonium or organic ammonium cation;
R22, R25, R32, R36, R41, R45 R54, R59, R63, R68, R72, R77, R78, R81 and R87 are, independently of one another, hydrogen,
Cχ-C -alkyl, Cχ-C4-haloalkyl, C2-C6-alkenyl, C2-Cg-halo- alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, Cχ-C4-cyano- alkyl, benzyl or optionally substituted phenyl;
R24, R27 and R28 are, independently of one another, hydrogen, Cχ-Cχo-alkyl optionally substituted with one to six halogens, one Cx-Cβ-alkoxy group, CO-OR3!, c(0)R32, C(OR33)2, C(SR34)2, C0-NR35R36, C(0)0N=CR37R38, cyano, optionally substituted phenyl or C(0)NH-0R39; C2-Cχo-alkenyl optionally substituted with one Cχ-Cg-alkyl group, one to three halogens, one Ci-Cε-alkoxy group, CO-OR4°, C(0)R41, C(OR2)2, C(SR3)2, CO-NR44R5, C(0)ON=CR46R47, cyano, optionally substituted phenyl or C(0)NH-OR48; c 3-C8-cycloalkyl optionally substituted with one Cχ-Cg- alkyl group, one to three halogens, one Ci-Cβ-alkoxy group, CO-OR49, C(0)R50, C(0R5l)2, C(SR52)2, CO-NR53R54, C(0)ON=CR55R56, cyano, optionally sub- stituted phenyl or C(0)NH-OR57;
Cs-Cδ-cycloalkenyl optionally substituted with one Cx-Cg- alkyl group, one to three halogens, one Cχ-C4-alkoxy group, CO-OR58, C(0)R59, C(OR60)2, C(SR61)2, C(0)NR62R63, C(O)0N=CR64R65, cyano, optionally sub- stituted phenyl or C(0)NH-OR66;
C3-C8-alkynyl optionally substituted with one Cχ-C6-alkoxy group, CO-OR67, C(0)R68, C(OR69)2, C(SR70)2, C0-NR7iR72, C(0)ON=CR73R74, cyano, optionally substituted phenyl or C(0)NH-OR75; phenyl optionally substituted with one to three halogens, one to three Cx-Cβ-alkyl groups, one to three Cχ-Cg- alkoxy groups, one to three Cχ-C6-haloalkyl groups, one to three Cχ-C6-haloalkoxy groups, one cyano, one nitro, one NR76R77, one C(0)R78 or one CO-OR79 group;
R30 is hydroxy, Cχ-C8-alkyl, C3-C8-cycloalkyl, Cχ-Cs-haloalkyl, C2-Cs-alkenyl, C2-C8-haloalkenyl, C3-C8-alkynyl, optionally substituted phenyl, optionally substituted benzyl or NR80R8l;
B and βi are, independently of one another, oxygen, sulfur or NRi7;
X2 and X3 are, independently of one another, oxygen or sulfur;
and the optical isomers and diastereomers thereof.
More preferred are those compounds of formula I wherein
Q is Q24; R is Cχ-C3-alkyl;
R2 is Cχ-C3-haloalkyl;
X is hydrogen or halogen; χi is hydrogen;
Z is sulfur; Y is selected from γl, Y2, Y3, Y4, γ5, γ6, yiθf γiif γi4f γi5,
Ylβ, Y 2, γ24f γ25, γ26f γ27f y28, y38 and y39# Ri5, RX8, R20 and R2χ are, independently of one another, hydrogen, Cχ-C3-alkyl, Cχ-C3-haloalkyl, Cχ-C3-alkoxy, halogen, hydroxy or, when R20 and R21 are attached to the same carbon of Y25, an epoxide ring is formed;
R16 is hydrogen, halogen, Cχ-C3-alkyl optionally substituted with C(0)R22, CO-OR23, χ2R24 or s(0)m-alkyl, or is phenyl; Cχ-C3-haloalkyl, C(0)R25, CO-OR26, χ3 27f C3-C8-cycloalkyl, N(R29)-S02-R3° or C2-C4-alkenyl;
Rl? is hydrogen, Cχ-C3-alkyl, C2-C4-alkenyl or C(0)R25;
R19, R29 and R80 are, independently of one another, hydrogen or
Cχ-C3-alkyl;
R22, R25 and R8i are, independently of one another, hydrogen,
Cχ-C3-alkyl, benzyl or optionally substituted phenyl;
R23, R 6 and R3I are, independently of one another, hydrogen, Cχ-C3-alkyl, C2-C4-alkenyl or C3-C6-alkynyl;
R24 and R27 are, independently of one another, hydrogen or Cχ-C3- alkyl optionally substituted with one CO-OR3i group or one
Cχ-C3-alkoxy group;
R30 is Cχ-C3-alkyl, C3-C5-cycloalkyl, Cχ-C3-haloalkyl, C2-C4-al- kenyl, optionally substituted phenyl, optionally substituted benzyl or NR80R8l;
X2 and X3 are, independently of one another, oxygen.
Most preferred compounds of formula I are those wherein Q is
Figure imgf000012_0001
Y is selected from
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
Figure imgf000013_0004
Figure imgf000014_0001
Ri5, Ri8, R20 and R2X are, independently of one another, hydrogen, C -C3-alkyl, Cχ-C3-haloalkyl or Cχ-C3-alkoxy;
Ri6 is hydrogen, halogen, Cχ-C8-alkyl optionally substituted with X2R24, Cχ-C3-haloalkyl, phenyl or C2-C4-alkenyl;
R17 is hydrogen, methyl or C(0)R25;
Ri9 is hydrogen or Cχ-C3-alkyl; R2 is hydrogen or Cχ-C3-alkyl;
R25 is Cχ-C3-alkyl or phenyl ;
X2 is oxygen .
R88 is preferably Cχ-C-haloalkyl, Cχ-C4-haloalkoxy or Cχ-C4-alkyl- sulfonyl, in particular trifluoromethyl or difluoromethoxy;
R88 is preferably hydrogen or halogen, in particular chlorine or bromine.
Formula I compounds of the present invention which are particularly effective herbicidal agents include l-methyl-3-[ 3-( 3-thienyl ) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; ethyl (R)-2-[5-[3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl) -1 (2H) -pyrimidinyl]-1,2-benzisothiazol-3-yl] -4-thi- azolidinecarboxylate; l-methyl-3-[3-(2-thienyl) -1,2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 3-methyl-2-thienyl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; l-methyl-3-[3-( l-methylimidazol-2-yl)-1,2-benzisothiazol-5-yl]- 6-(trifluoromethyl)uracil; l-methyl-3-[3-( l-methylpyrrol-2-yl) -1,2-benzisothiazol-5-yl] - 6-(trifluoromethyl) racil; l-methyl-3-[ 3-( 4-methyl-2-thiazolyl) -1,2-benzisothiazol-5-yl]- 6-(trifluoromethyl)uracil; 3-[ 3-( 2 , 5-diethyl-3-thienyl) -1, 2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-pyrodyl) -1 ,2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; 3-[ 3-( 3-methoxy-2-thienyl ) -1 , 2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 3-pyridyl) -1,2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[ 3-(2-pyrimidinyl ) -1,2-benzisothiazol-5-yl]-6-(trifluoromethyl )uracil; 3-[ 3-[ ( IR, 2S) -1 ,2-epoxypropyl] -1, 2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl) racil;
3-[ 3-[ ( IR, 2R) -1, 2-epoxypropyl] -1, 2-benzisothiazol-5-yl]-1-methyl- 6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-pyridyl ) -1, 2-benzisothiazol-5-yl]-6-(trifluoro- methyl)uracil N' ' ,S,S-trioxide; l-methyl-3-[ 3-( 5-methyl-l, 3, 4-oxadiazol-2-yl)-1,2-benzisothiazol- 5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[3-(5-methyl-l,3, 4-thiadiazol-2-yl)-1,2-benzisothi- azol-5-yl] -6-(trifluoromethyl)uracil;
1, -benzisothiazole-3-carboxanilide, 4 '-chloro-5-[ 3 , 6-dihydro- 3-methyl-2 , 6-dioxo-4-(trifluoromethyl) -1 ( 2H)-pyrimidinyl] - N-methyl-; l-methyl-3-[3-(3-methyl-2-pyridyl)-1,2-benzisothiazol-5-yl]- 6-(trifluoromethyl)uracil;
N-[3-( 5-methyl-2-thienyl) -1, 2-benzisothiazol-5-yl] -1-cyclohexene- 1,2-dicarboximide; l-methyl-3-[ 3-( 5-methyl-2-thienyl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; methyl [ (2-[5-[3, 6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl) -1 ( 2H) -pyrimidinyl] -1, 2-benzisothiazol-3-yl] - 3-thienyl]oxy]acetate; methyl 2-[(2-[5-[3, 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl]- 3-thienyl]oxy]propionate;
3-[3-( 1, 3-dithiolan-2-yl) -1, 2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil; 3-[ 6-fluoro-3-( 2-pyridyl ) -1, 2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 4-methyl-3-thienyl) -1,2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; 3-[ 3-( 3 , 5-dimethyl-2-thienyl ) -1, 2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil;
3-(3-m-dioxan-2-yl-l,2-benzisothiazol-5-yl)-l-methyl-6-(trifluoromethyl)uracil;
3-acetyl-2-[ 5-[ 3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl) -1 ( 2H) -pyrimidinyl] -1,2-benzisothiazol-3-yl]thiazolidine; 3-benzoyl-2-[ 5-[ 3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl) -1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl] hiazolidine; l-methyl-3-[ 3-( l,3-oxathiolan-2-yl)-l,2-benzisothiazol-5-yl]- 6-(trifluoromethyl)uracil; l-methyl-3- [ 3-( 1 , 3-oxathioln-2-yl) -1,2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil S ', S ' -dioxide;
1,2-benzisothiazole-3-carboxaldehyde, 5-[3 , 6-dihydro-3-methyl- 2, 6-dioxo-4-(trifluoromethyl ) -1 (2H) -pyrimidinyl]-, 3-[bis(2-hydroxyethyl) dithioacetal] ; l-methyl-3-[ 3-( 1 , 3-oxathian-2-yl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; l-methyl-3-[3-( 1 ,3-oxathian-2-yl)-1,2-benzisothiazol-5-yl]- 6-(trifluoromethyl)uracil S' ,S'-dioxide;
3-[3 (5, 5-dimethyl-m-dioxan-2-yl) -1,2-benzisothiazol-5-yl]- l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-(4-methyl-m-dioxan-2-yl)-l,2-benzisothiazol-5-yl]- 6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 3-methylpyrazol-l-yl) -1, 2-benzisothiazol-5-yl] -
6-(trifluoromethl)uracil;
2-propynyl [ [2-[5-[3, 6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl) -1 (2H) -pyrimidinyl]-1,2-benzisothiazol-3-yl] - 3-thienyl]oxy]acetate;
3-[ 3-( 4 , 6-dimethyl-2-pyrimidinyl) -1 , 2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-( 3-methoxy-2-pyridyl) -1, 2-benzisothiazol-5-yl] -1-methyl-
6-(trifluoromethyl)uracil; l-methyl-3-[3-( 5-methyl-2-pyridyl) -1, 2-benzisothiazol-5-yl] -
6-(trifluoromethyl)uracil;
3-[ 3-( 4 , 6-diethoxy-2-pyrimidinyl) -1 , 2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil;
3-[ 6-fluoro-3-( 3-methyl-2-pyridyl) -1,2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-( 1, 3-dioxolan-2-yl) -1,2-benzisothiazol-5-yl] -1-methyl-
6-(trifluoromethyl)uracil;
N-[ 6-fluoro-3-( 3-methyl-2-pyridyl ) -1 , 2-benzisothiazol-5-yl] -
1-eyelohexene-1, 2-diearboximide; 3-[ 3-[ ( 4R, 5S) -4 , 5-dimethyl-l, 3-dioxolan-2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-[ ( 4R, 5R) -4,5-dimethyl-l, 3-dioxolan-2-yl] -1,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-6-(trifluoromethyl)-3-[ 3-( 3 , 4 , 5-trimethylpyrazol-l-yl)- 1, 2-benzisothiazol-5-ylJuracil;
3-[ 3-[ ( 4R, 6S) -4 , 6-dimethyl-m-dioxan-2-yl] -1, 2-benzisothiazol-
5-yl] -l-methyl-6-(trifluoromethyl )uracil;
3-[ 3-[ ( 4R, 6S) -4, 6-dimethyl-m-dioxan-2-yl] -1 ,2-benzisothiazol-
5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[ 3-( 3-chloro-2-thienyl) -1,2-benzisothiazol-5-yl]-1-methyl-
6- (trifluoromethyl)uracil; l-methyl-3-[ 3-( 2-thiazolyl) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 2-methyl-1, 3-dioxolan-2-yl ) -1,2-benzisothiazol- 5-yl] -6-(trifluoromethyl)uracil; l-methyl-6- (trifluoromethyl) -3-[3-( 4,4, 6-trimethyl-m-dioxan-
2-yl)-l,2-benzisothiazol-5-ylJuracil; l-methyl-3-[ 3-( 4,4,5, 5-tetramethyl-l, 3-dioxolan-2-yl) -1, 2-benz- isothiazol-5-yl] -6-(trifluoromethyl )uracil; l-methyl-3-[ 3-(4-methyl-l, 3-dioxolan-2-yl ) -1, 2-benzisothiazol-
5-yl] -6-(trifluoromethyl)uracil;
2 , 4 ( 1H, 3H) -pyrimidinedione, l-methyl-3-[ 3-( 5-methylene-m- dioxan-2-yl) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl) -; l-methyl-3-[ 3- ( 4-methylpyrazol-l-yl) -1,2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil;
3-[ 3-(2-furyl) -1 , 2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[3-( 1, 3-dioxolan-2-yl)-6-fluoro-1 ,2-benzisothiazol-5-yl]- l-methyl-6-(trifluoromethyl)uracil;
3-( 3-m-dioxan-2-yl-6-fluoro-1, 2-benzisothiazol-5-yl) -1-methyl-
6-( rifluoromethyl)uracil; 3-[3-[ (4R,5S)-4,5-dimethyl-l,3-dioxolan-2-yl]-6-fluoro-1,2-benz- isothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-[ 4-(methoxymethyl) -1, 3-dioxolan-2-yl] -1,2-benzisothiazol-
5-yl]-l-methyl-6-( rifluoromethyl)uracil;
3-[3-(3, 6-dihydro-4,6,6-trimethyl-2H-pyran-2-yl) -1,2-benziso- thiazol-5-yl] -l-methyl-6-( rifluoromethyl)uracil;
3-[ 3-[ ( 4R, 5S-) -4 , 5-dimethyl-l, 3-dioxolan-2-yl]-6-fluoro-1 ,2-benz- isothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[3-[ (4R, 6S)-4 , 6-dimethyl-m-dioxan-2-yl]-6-fluoro-1,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 2 , 4 ( IH, 3H) -pyrimidinedione, l-methyl-3-[ 3-(2-methyl-3-thienyl) -
1,2-benzisothiazol-5-yl]-6-(trifluoromethyl) -;
3-[3-[5-(bromomethyl)-5-hydroxy-m-diaxan-2-yl]-1,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-( 3-spiro[m-dioxane-5,2 '-oxiran] -2-yl-l,2-benziso- thiazol-5-yl) -6-(trifluoromethyl)uracil;
3-[3-(4,4-dimethyl-5-oxo-l,3-dioxolan-2-yl) -1,2-benzisothiazol-
5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-[ 4-(chloromethyl ) -1, 3-dioxolan-2-yl] -1,2-benzisothiazol-
5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[ 3-[4-(hydroxymethyl) -1 , 3-dioxolan-2-yl] -1,2-benzisothiazol-
5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-( 4-isopropyl-2-oxazolin-2-yl) -1,2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[ 3 (2-oxazolin-2-yl) -1, 2-benzisothiazol-5-yl] -6-(tri- fluoromethyl)uracil; l-methyl-6-(trifluoromethyl ) -3-[ 3-( 4-vinyl-l ,3-dioxolan-2-yl) -
1, 2-benzisothiazol-5-yl]uracil; l-methyl-3-[ 3- ( 4-propyl-l, 3-dioxolan-2-yl) -1,2-benzisothiazol-
5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 4-phenyl-l , 3-dioxolan-2-yl) -1,2-benzisothiazol-
5-yl] -6-(trifluoromethyl)uracil;
3-[ 3-[4-(bromethyl) -1, 3-dioxolan-2-yl] -1,2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-[ 3-(bromomethl) -2-thienyl] -1, 2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-[ 3-(methoxymethyl) -2-thienyl] -1, 2-benzisothiazol-5-yl]- l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-( 3, 4-dimethyl-2-thienyl) -1, 2-benzisothiazol-5-yl] -1-methyl-
6-(trifluoromethyl)uracil; 3-[ 3-( 3-furyl) -1, 2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-[4-[ (methylthio)methyl] -1,3-dioxolan-2-yl)-
1,2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil;
3-[3-[3-(hydroxymethyl)-2-thienyl]-1 ,2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-[4-[ (methylsulfonyl)methyl]-1,3-dioxolan-2-yl]- l,2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[3-[ 4-[ (methylsulfonyl)methyl] -1, 3-dioxolan-2-yl] -
1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[3-[ 4-[ (methylsulfinylJmethyl] -1, 3-dioxolan-2-yl] - 1,2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil;
[ 2-[ 5-[ 3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl) -1 (2H) - pyrimidinyl]-1,2-benzisothiazol-3-l]-1, 3-dioxolan-4-yl]methyl thiocyanate;
3-[ 3-(3 , 4-dihydro-3-oxo-2-quinoxalinyl) -1, 2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil;
5-[ 5-[ 3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl) -
1(2H) -pyrimidinyl] -1,2-benzisothiazol-3-yl] -1,6-hydro-6-oxo-
2 , 3-pyrazinedicarbonitrile; l-methyl-3-[3-(4-oxo-delta-2-l,2,5-thiadiazolin-3-yl)-1,2-benz- isothiazol-5-yl]-6-(trifluoromethyl)uracil S' ,S'-dioxide;
3-[3-[2-(dimethylamino)-4-methoxy-5-oxo-2-imidazolin-4-yl]-
1,2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-( 4-hydroxy-5-oxo-2-phenyl-2-imidazolin-4-yl ) -1,2-benziso- thiazol-5-yl]-l-methyl-6-(trifluoromethyl)uracil; 3-[3-(2-tert-butyl-4-hydroxy-5-oxo-2-imidazolin-4-yl)-l,2-benz- isothiazol-5-yl]-l-methyl-6-(trifluoromethyl)uracil;
3-[3-(4-hydroxy-5-imino-4 , 4-dimethyl-2-oxo-3-pyrrolidinyl) - l,2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[3[4-methoxy-2-(methylimino)-5-oxo-4-imidazolidinyl]-l,2-benz- isothiazol-5-yl]-l-methyl-6-(trifluoromethyl)uracil and
3-[ 3 [4-methoxy-2-(ethylimino) -5-oxo-4-imidazolidinyl] -1,2-benz- isothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil.
The compounds of formula I of the present invention are effective herbicidal agents useful for the control of a wide variety of undesirable plant species and for controlling weeds native to both dry land and wet land areas. The inventive compounds are effective in controlling the above-said plants when applied to the foliage thereof or to the soil or water containing seeds or other propagating organs thereof such as stolons, tubers or rhizomes, at rates of from about 0.01 kg/ha to 4 kg/ha and preferably from about 0.01 kg/ha to 1 kg/ha. Advantageously, it has been found that the compounds of this invention are selective in the presence of soybeans and/or cereal crops such as corn, wheat and rice when applied preemergence or postemergence.
Beneficially, the compounds of formula I may be used for the selective control of undesirable plant species in transplanted rice culture by applying a herbicidally effective amount of a formula I compound to the soil or water containing seeds or other propagating organs of said undesirable plant species after the rice has been transplanted.
Those compounds of formula I which are especially useful for the selective control of undesirable plant species in the presence of corn include l-methyl-3-[3-(3-thienyl)-1,2-benzisothiazol-5-yl]-6-(trifluorome hyl)uracil;
3-[3-(3-chloro-2-thienyl) -1,2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil; 3-[ 3-(3 , 4-dimethyl-2-thienyl) -1 , 2-benzisothiazol-5-yl]-1-methyl- 6-(tri luoromethyl)uracil;
3-[ 3-[ ( R, 5S )-4 , 5-dimethyl-l, 3-dioxolan-2-yl]-1 , 2-benzisothiazol- 5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[ 3-[ ( 4R, 5R) -4 , 5-dimethyl-l, 3-dioxolan-2-yl] -1 , 2-benzisothiazol- 5-yl] -l-methyl-6-(trifluoromethyl)uracil and ethyl (R) -2-[ 5-[ 3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl) -1 ( 2H)-pyrimidinyl] -1, 2-benzisothiazol-3-yl] -4-thi- azolidinecarboxylate.
Those compounds of formula I which are particularly useful for the selective control of undesirable plant species in the presence of wheat include l-methyl-3- [3-( 3-thienyl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-thienyl) -1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 3-methyl-2-thienyl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 5-methyl-2-thienyl) -1 ,2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil;
3-[ 3-( 3-chloro-2-thienyl ) -1,2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil;
3-[3-(3, 4-dimethyl-2-thienyl) -1,2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil; 3-[3-(2,5-diethyl-3-thienyl)-1,2-benzisothiazol-5-yl]-1-methyl- 6-(trifluoromethyl)uracil; 3-[3-(3-methoxy-2-pyridyl) -1,2-benzisothiazol-5-yl] -1-methyl-
6-(trifluoromethyl)uracil;
3-[3-[ (4R, 5S) -4,5-dimethyl-l,3-dioxolan-2-yl]-1 ,2-benzisothiazol-
5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[3-[ (4R,r% )-4 , 5-dimethyl-l,3-dioxolan-2-yl]-6-fluoro-1,2-benz- isothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[3-[ 4-(hydroxymethyl) -1, 3-dioxolan-2-yl] -1 , 2-benzisothiazol-
5-yl]-l-methyl-6-(trifluoromethyl)uracil; l-methyl-6-(trifluoromethyl) -3-[ 3-( 4-vinyl-l,3-dioxolan-2-yl)- 1,2-benzisothiazol-5-yl]uracil; l-methyl-3-[ 3-( 4-propyl-l, 3-dioxolan-2-yl) -1,2-benzisothiazol-
5-yl]-6-(trifluoromethyl)uracil;
3-[ 3-[ 4-(bromethyl ) -1, 3-dioxolan-2-yl] -1, 2-benzisothiazol-5-yl]- l-methyl-6-(trifluoromethyl)uracil; 3-[ 3-( 4-isopropyl-2-oxazolin-2-yl) -1, 2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil and ethyl (R) -2-[5-[3, 6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl) -1 (2H) -pyrimidinyl]-1,2-benzisothiazol-3-yl] -4-thiazolidi- necarboxylate.
Formula I compounds of this invention which are particularly useful for the selective control of undesirable plant species in the presence of soybeans include l-methyl-3-[3-(3-thienyl)-1,2-benzisothiazol-5-yl]-6-(trifluoro- methyl)uracil;
3-[3-(3-Methoxy-2-thienyl)-1,2-benzisothiazol-5-yl]-1-methyl-
6-(trifluoromethyl )uracil; l-methyl-3-[ 3-( 5-methyl-2-thienyl) -1, 2-benzisothiazol-5-yl] -
6-(trifluoromethyl)uracil; 3-[3-(3-chloro-2-thienyl)-l,2-benzisothiazol-5-yl] -1-methyl-
6-(trifluoromethyl)uracil;
3-[ 3-( 3, 4-dimethyl-2-thienyl ) -1,2-benzisothiazol-5-yl] -1-methyl-
6-(trifluoromethyl)uracil;
3-[ 3-( 3-methoxy-2-pyridyl) -1, 2-benzisothiazol-5-yl]-1-methyl- 6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 5-methyl-2-pyridyl) -1 , 2-benzisothiazol-5-yl] -
6-( rifluoromethyl )uracil;
3-[3-[4-(hydroxymethyl) -1, 3-dioxolan-2-yl] -1,2-benzisothiazol-
5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-pyrimidinyl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil;
3-[3-[ (4R,6S) -4, 6-dimethyl-m-dioxan-2-yl] -6-fluoro-1,2-benziso- thiazol-5-yl]-l-methyl-6-(trifluoromethyl)uracil and
3-[3-( 4-isoproρyl-2-oxazolin-2-yl)-1,2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil. Formula I compounds of this invention which are particularly useful for the selective control of undesirable plant species in the presence of transplanted rice include l-methyl-3-[ 3-( 5-methyl-2-thienyl) -1,2-benzisothiazol-5-yl] -
6- trifluoromethyl)uracil;
3- 3-(3-chloro-2-thienyl)-1,2-benzisothiazol-5-yl]-1-methyl-
6- trifluoromethyl)uracil;
3- 3-[ 3-(methoxymethyl) -2-thienyl]-1, 2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil;
3- 3-(3 , 4-dimethyl-2-thienyl) -1,2-benzisothiazol-5-yl] -1-methyl-
6- trifluoromethyl)uracil;
3- 3-( 2 , 5-diethyl-3-thienyl)-1 ,2-benzisothiazol-5-yl] -1-methyl-
6- trifluoromethyl)uracil;
3- 6-fluoro-3-(2-pyridyl) -1,2-benzisothiazol-5-yl] -1-methyl-
6- trifluoromethyl)uracil;
3- 3-(3-methoxy-2-pyridyl)-1,2-benzisothiazol-5-yl]-1-methyl-
6- trifluoromethyl)uracil; l-methyl-3-[ 3-( 5-methyl-2-pyridyl) -1, 2-benzisothiazol-5-yl ] -
6- trifluoromethyl)uracil; 3- 6-fluoro-3-( 3-methyl-2-pyridyl) -1,2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil;
3- 3-( 1, 3-dioxolan-2-yl) -1,2-benzisothiazol-5-yl] -1-methyl- 6- trifluoromethyl)uracil; 3- 3-[ ( 4R,5S) -4, 5-dimethyl-l, 3-dioxolan-2-yl]-1, 2-benzisothiazol- 5-yl ] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-methyl-l, 3-dioxolan-2-yl)-1,2-benzisothiazol- 5-yl] -6-(trifluoromethyl)uracil;
3-[3-[ ( 4R,r% ) -4 , 5-dimethyl-l, 3-dioxolan-2-yl] -6-fluoro-1, 2-benz- isothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-6-(trifluoromethyl) -3-[ 3-( -vinyl-l, 3-dioxolan-2-yl ) - 1,2-benzisothiazol-5-yl]uracil; l-methyl-3-[ 3-( 4-propyl-l, 3-dioxolan-2-yl ) -1, 2-benzisothiazol- 5-yl] -6-(trifluoromethyl)uracil;
3-[ 3-( 4-isopropyl-2-oxazolin-2-yl) -1 ,2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-thiazolyl)-1,2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil and ethyl (R) -2-[5-[3, 6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl) -1 ( 2H) -pyrimidinyl] -1,2-benzisothiazol-3-yl] -4-thi- azolidinecarboxylate.
Formula I compounds of this invention which are particularly useful for total vegetation control include
3-[3-( 1, 3-dioxolan-2-yl) -1, 2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil; l-methyl-3-[3-(4-methyl-l,3-dioxolan-2-yl)-l,2-benzisothiazol- 5-yl] -6-(trifluoromethyl)uracil; 3-[3-( 1,3-dioxolan-2-yl)-6-fluoro-1,2-benzisothiazol-5-yl]- l-methyl-6-( rifluoromethyl)uracil;
3-[ 3-[4-(methoxymethyl) -1,3-dioxolan-2-yl] -1,2-benzisothiazol- 5-yl]-l-methyl-6-(trifluoromethyl)uracil; 3-[3-[ (4R,5S-) -4 , 5-dimethyl-l,3-dioxolan-2-yl] -6-fluoro-1,2-benz- isothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-(3-m-dioxan-2-yl-l,2-benzisothiazol-5-yl) -l-methyl-6-(trifluoromethyl )uracil;
3-[ 3-[ ( R, 6S) -4 , 6-dimethyl-m-dioxan-2-yl]-1, 2-benzisothiazol- 5-yl]-l-methyl-6-(trifluoromethyl)uracil and
3-( 3-m-dioxan-2-yl-6-fluoro-1, 2-benzisothiazol-5-yl) -1-methyl- 6-( rifluoromethyl)uracil.
While the compounds of this invention are effective for controlling undesirable plant species when employed alone, they may also be used in combination with or in conjunction with one or more other biological chemicals, including herbicides.
The compounds of this invention may be applied to the foliage of undesirable plant species or to the soil or water containing seeds or other propagating organs thereof in the form of a solid or liquid herbicidal composition, comprising a herbicidally effective amount of the desired compound dispersed or dissolved in an agronomically acceptable, inert solid or liquid carrier. The compositions may be applied as preemergence or postemergence treatments .
The formula I compounds of the present invention may be formulated as emulsifiable concentrates, wettable powders, granular formulations, suspension concentrates, flowable concentrates and the like.
Formula I compounds wherein Q is Q1, Q2, Q3, Q5, Q6, Q7, Q9, Q10, QH, Q12, QI3, Qi , Q16, Q17, Q18, Q19, Q20, Q22, Q24, Q25. Q36 and Q« may be prepared from 5-aminobenzisothiazoles and 5-aminobenziso- xazoles of Formula II
Figure imgf000023_0001
wherein X, X1, Z and Y are as described hereinabove, using essentially the same procedures as described in US 5,484,763 and US 5,523,278. Formula I compounds wherein Q is Q8 may be prepared by reacting an amine of formula II with a substituted tetrahydrofuran of formula III as shown below in Flow Diagram I.
FLOW DIAGRAM I
Figure imgf000024_0001
(ID
Figure imgf000024_0002
Formula I compounds wherein Q is Q4 may be prepared from formula I compounds wherein Q is Q8 using essentially the same procedures used to prepare formula I compounds wherein Q is Q3 from formula I compounds wherein Q is Q7.
Compounds of formula I wherein ζ> is Qi5 may be prepared by reacting an amine of formula II with a substituted tetrahydrofuran of formula III to form an acid-amide of formula IV, and dehydrating the acid-amide with a dehydrating agent such as 1,3-dicyclohexyl- carbodiimide. The reaction scheme is shown below in Flow Diagram !!• FLOW DIAGRAM II
Figure imgf000025_0001
I (Q = Q15)
Formula I compounds wherein Q is Q2i may be prepared from formula I compounds wherein Q is Q8 using essentially the same procedure used to prepare formula I compounds wherein Q is Q20 from formula I compounds wherein Q is Q7.
Compounds of formula I wherein Q is Q23 may be prepared by converting an amine of formula II to its corresponding isocyanate or isothiocyanate of formula V using standard methods such as phosgene or thiophosgene in an inert solvent or palladium chloride and carbon monoxide, reacting the formula V compound with a substituted hydrazine of formula VI to form an intermediate compound of formula VII, and reacting the formula VII compound with an ester of formula VIII. The reaction scheme is shown in Flow Diagram III. FLOW DIAGRAM III
Figure imgf000026_0001
(II)
Cl—u—Cl or PdCl,/CO
Figure imgf000026_0002
RNHNH2 (VI)
Figure imgf000026_0003
Formula I compounds wherein Q is Q26 may be prepared by reacting an amine of formula II with a β-aminoacrylic acid chloride of formula IX to form an intermediate compound of formula X, and reacting the intermediate compound with an acid chloride of formula XI. The reaction scheme is shown in Flow Diagram IV. FLOW DIAGRAM IV
Figure imgf000027_0001
Compounds of formula I wherein Q is Q27 may be prepared by reacting an amine of formula II with an acid chloride of formula XII to form an intermediate compound of formula XIII, and reacting the intermediate compound (after deprotection) with an acid chloride of formula XI. The reaction sequence is shown below in Flow Diagram V. FLOW DIAGRAM V
te roup)
Figure imgf000028_0001
Figure imgf000028_0002
Formula I compounds wherein Q is Q28 may be prepared by reacting an amine of formula II with an unsaturated lactone of formula XIV as shown below in Flow Diagram VI. FLOW DIAGRAM VI
Figure imgf000029_0001
Similarly, formula I compounds wherein Q is 29 may be prepared by reacting an amine of formula II with a lactone of formula XV. The reaction scheme is shown in Flow Diagram VII.
FLOW DIAGRAM VII
Figure imgf000030_0001
Compounds of formula I wherein Q is Q30 may be prepared, as shown in Flow Diagram VIII, by reacting an isocyanate or isothiocyanate of formula V with an unsaturated lactone of formula XVI at an elevated temperature.
FLOW DIAGRAM VIII
Figure imgf000031_0001
(V)
Figure imgf000031_0002
Similarly, formula I compounds wherein Q is Q3l may be prepared by reacting an isocyanate or isothiocyanate of formula V with a lactone of formula XVII at an elevated temperature. The reaction scheme is shown in Flow Diagram IX.
FLOW DIAGRAM IX
Figure imgf000032_0001
(V)
Figure imgf000032_0002
Formula I compounds wherein Q is Q34 may be prepared, as shown in Flow Diagram X, by reacting an isocyanate or isothiocyanate of formula V with a substituted hydrazine of formula XVIII to form an intermediate compound of formula XIX, and reacting the formula XIX compound with an acetal of formula XX at an elevated temperature .
FLOW DIAGRAM X
Figure imgf000033_0001
RNHNHR^ (XVIII)
Figure imgf000033_0002
Δ R4R5C(OCH5)2 (XX)
Figure imgf000033_0003
Formula I compounds wherein Q is Q37 may be prepared, as shown in Flow Diagram XI, by reacting an isocyanate or isothiocyanate of formula V with an amine of formula XXI to form an intermediate of formula XXII, and reacting the intermediate with an α-haloketone of formula XXIII. FLOW DIAGRAM XI
Figure imgf000034_0001
Compounds of formula II wherein Q is Q38 may be prepared, as shown below in Flow Diagram XII, by reacting a urea or thiourea of formula VII with an acid chloride of formula XXIV. FLOW DIAGRAM XII
Figure imgf000035_0001
Formula I compounds wherein Q is Q39 may be prepared by reacting an amine of formula II with a chloride compound of formula XXV to form an intermediate compound of formula XXVI, and reacting the intermediate compound with hydrogen sulfide, hydrogen chloride and sodium periodate. The reaction scheme is shown in Flow Diagram XIII.
FLOW DIAGRAM XIII
Figure imgf000036_0001
Compounds of formula I wherein Q is Q35 may be prepared from amine compound II by treatment with nitrous acid to form an intermediate diazonium salt XXVII followed by treatment with cuprous cyanide and heating to afford an intermediate cyano compound of formula XXVIII. Treatment of the intermediate cyano compound XXVIII with a substituted hydrazine of formula VI to form an intermediate compound of formula XXIX, and reacting the intermediate compound with an acid chloride of formula XXX. The reaction scheme is show in Flow Diagram XIV. FLOW DIAGRAM XIV
Figure imgf000037_0001
NaN02 HC1
Figure imgf000037_0002
(XXVIII)
Figure imgf000037_0003
(XXIX)
Figure imgf000037_0004
Compounds of formula I wherein Q is Q33 may be prepared, as shown in Flow Diagram XV, by acylating a compound of formula XXXI with acetyl chloride and aluminum chloride to form an acetophenone of formula XXXII, reacting the acetophenone compound with an ester of formula XXXIII in the presence of a base to form a diketone compound of formula XXXIV, and reacting the formula XXXIV compound with a substituted hydrazine of formula VI.
FLOW DIAGRAM XV
Figure imgf000038_0001
(XXXII)
RCOO(C -C4-alkyl)
Base (XXXIII)
Figure imgf000038_0002
Further methods to prepare compounds I with Q = Q33 may be taken from EP-A 361 164 and WO 92/02509. Compounds of formula I wherein Q is Q32 may be prepared as shown in Flow Diagram XVI by reacting an isocyanate or isothiocyanate of formula V with an amidine of formula XXXV to form an intermediate of formula XXXVI, reacting the formula XXXVI compound with phosgene or thiophosgene to form an intermediate of formula XXXVII, and alkylating the formula XXXVII compound with a halide of formula XXXVIII.
FLOW DIAGRAM XVI
Figure imgf000039_0001
A preferred method for the preparation of formula I compounds wherein Q is Q24 is shown in Flow Diagram XVII, wherein an amine of formula II is reacted with an oxazinone of formula XXXIX in the presence of an organic acid or base to form an intermediate compound of formula XL, which is alkylated with a halide of formula XXXVIII.
FLOW DIAGRAM XVII
l)2
Figure imgf000040_0001
I (Q = Q24; A, Al = O)
Formula I compounds wherein Q = Q24 and the intermediates of formula XL may also be prepared from the amines II by using essentially the same procedures as described in WO 97/08171, WO 99/14216, WO 00/28822 and DE-A 197 50 195. Another preferred method for the preparation of intermediates XL is shown in Flow Diagram XVIII, by reaction of an amine of formula II with a urea of Formula XLI in the presence of an acid or base, wherein R82 and R83 are each independently Cχ-Cg-alkyl or Rδ and R83 may be taken together with the atom to which they are attached to form a 5- or 6-membered ring optionally containing one oxygen atom.
FLOW DIAGRAM XVIII
Figure imgf000041_0001
I (Q = Q24; A, Al = 0)
An alternate method for the preparation of formula I compounds wherein Q is Q24 is shown in Flow Diagram XIX, wherein an amine of formula II is reacted with a carbamate of formula XLII wherein R84 is Cχ-C6-alkyl, benzyl, C2-C6-alkenyl, C2-C6-alkynyl or C3-C7- cycloalkyl and Z2 is Cχ-C6-alkyl.
FLOW DIAGRAM XIX
Figure imgf000042_0001
i (Q = = Q 24 . A Al = O) 5-Aminobenzisothiazole and 5-aminobenzisoxazole compounds of formula II can be prepared by reduction of 5-nitro intermediates of formula XLIV as shown in Flow Diagram XX using standard conditions such as iron in acetic acid, stannous chloride and hydrochloric acid, or dithionite. The 5-nitro intermediates XLIV can be prepared from ketones of formula XLIII by methods described in US 5,484,763, also shown in Flow Diagram XX.
FLOW DIAGRAM XX
( XLIII )
Figure imgf000043_0001
For Z = S For Z = 0
1 . S 1 . H,N0H
2 . NH4OH 2 . Base
Figure imgf000043_0002
Alternatively, 5-aminobenzisothiazoles of formula II may be prepared as shown in Flow Diagram XXI. Nitration of ketones of formula XLV followed by reduction of the resulting intermediates XLVI affords amines of formula XLVII. Treatment of formula XLVII compounds with sodium isothiocyanate and bromine in the presence of acid affords intermediate isothiocyanate compounds of formula XLVIII, which on treatment with ammonium hydroxide in methanol afford 5-aminobenzisothiazole compounds of formula II (Z = S). FLOW DIAGRAM XXI
Figure imgf000044_0001
HN03/H2S04
Figure imgf000044_0002
Ketones of formula XLIII where Y is Yx may be prepared by reaction of organolithium reagents XLIX with zinc chloride followed by coupling with acid chloride LI in the presence of a palladium catalyst as shown in Flow Diagram XXII. Under essentially the same conditions, ketones of formula XLIII where Y is Y are prepared from organometallic reagents L. Organometallic reagents XLIX and L may be prepared by standard methods such as direct deprotonation of the heterocycle Y, or by halogen-metal exchange with a halogenated heterocycle Y.
FLOW DIAGRAM XXII
Figure imgf000045_0001
( XLIII , Y = Y) (XLIII , Y = v)
Ketones of formula XLIII wherein Yx is a substituted 2-furanyl radical may additionaly be prepared by reaction of organotin reagent LII with acid chloride LI as shown in Flow Diagram XXIII .
FLOW DIAGRAM XXIII
Figure imgf000046_0001
(XLIII, Y=γ, B=0)
Ketones of formula XLIV wherein Y is a substituted 2- or 3-thienyl radical may additionally be prepared by reaction of thiophene LIV with acid chloride LI, in the presence of a Lewis acid such as aluminum chloride as shown in Flow Diagram XXIV. Al- ternatively, ketones of formula XLIV wherein Yx is a substituted 2-thienyl radical may be prepared by treatment of acid LIU with thiophene LIV in the presence of phosphorous pentoxide.
FLOW DIAGRAM XXIV
Figure imgf000047_0001
(XLIII, Y=χ, B=S)
Ketones of formula XLIV wherein Y is Y3 may be prepared by treatment of nitrile LV with lithiated pyridine LVII followed by acid hydrolysis to afford intermediate ketone compound LVII, which is nitrated under standard conditions as depicted in Flow Diagram XXV. Lithiated pyridine XLVIII may be prepared from the corresponding bromopyridine by treatment with n-butyllithium.
FLOW DIAGRAM XXV
Figure imgf000048_0001
(LVII)
H2S04
HNCg
Figure imgf000048_0002
Ketones of formula XLIV wherein Y is Y5 may be prepared by heating nitrile LVIII with bromopyrimidine LIX to afford intermediate LX, which on oxidation yields ketone LXI, which can be nitrated as depicted in Flow Diagram XXVI. FLOW DIAGRAM XXVI
Figure imgf000049_0001
HNO3 H2S04
Figure imgf000049_0002
(XLIII, Y= )
The aformentioned nitro ketones of formula XLIV where where Y is Yx, Y , Y3 and Y5 may be converted into nitro intermediate XLIV and amino intermediate II by the methods shown in Flow Diagram XX.
Ketones of formula XLV wherein Y is Y may be prepared by reaction of nitrile LXII with organolithium reagent LXIV followed by hy- drolysis under acidic conditions as shown in Flow Diagram XXVII. Alternatively, ketones XLV wherein Y is Y may be prepared by reaction of Grignard reagent LXIII with pyridylnitrile LXV folio- wed by hydrolysis under acidic conditions as shown in Flow Diagram XXVII.
FLOW DIAGRAM XXVII
Figure imgf000050_0001
XLV (Y="-f)
The aforementioned ketones XLV wherein Y is Y3 may be converted to 5-aminobenzisoxazoles and 5-aminobenzthiazoles wherein Y is Y3 by the method outlined in Flow Diagram XXI.
Compounds of formula I wherein Y is Y and B=S additionally may be prepared by treatment of thioamide LXVI with a bromoketone of formula LXVII in the presence of base as shown in Flow Diagram XXVIII. FLOW DIAGRAM XXVIII
Figure imgf000051_0001
(I, Y=Y, B=S)
Intermediate thioamide compound of formula LXVI can be prepared by standard methods such as treatment amide compound of formula LXX with Lawson's reagent or phosphorous pentasulf ide. Formula LXX amides are prepared from acid LXVIII by treatment of its acid chloride derivative LXIX with ammonia as depicted in Flow Diagram XXIX.
FLOW DIAGRAM XXIX
Figure imgf000052_0001
(LXVIII)
Figure imgf000052_0002
Intermediate acid compounds of formula LXVIII may be prepared by bromination of methyl intermediate LXXI to afford a mixture of monobromo (LXXII) and dibromo (LXXIII) intermediate compounds, subsequent oxidation of this mixture with silver tetrafluorobo- rate to afford a mixture of alcohol LXXIV and aldehyde LXXV, and final oxidation of this mixture with potassium dichromate in the presence of acid as shown in Flow Diagram XXX. FLOW DIAGRAM XXX
Figure imgf000053_0001
NBS
Figure imgf000053_0002
Figure imgf000053_0003
(LXXII) (LXXIII)
AgBF,
Figure imgf000053_0004
(LXVIII)
Compounds of formula I where Y=Ys may additionally be prepared by oxidation of intermediate dibromo compound LXXIII to aldehyde LXXV followed by reaction with diketone LXXVI or imino ester LXXVII as depicted in Flow Diagram XXXI. FLOW DIAGRAM XXXI
Figure imgf000054_0001
(LXXIII)
Figure imgf000054_0002
(I, Y=Y5) (I, Y=Ys)
Compounds of formula I wherein Y is Y4 may be prepared by oxidation of pyridyl compounds of formula I (Y=Y3) with peracid under standard conditions as shown in Flow Diagram XXXII. FLOW DIAGRAM XXXII
Figure imgf000055_0001
(I, Y=3)
30% H s HOAC
Figure imgf000055_0002
( i , Y=V
Nitro intermediates XLIV and benzisothiazoles and benzisozaxoles II wherein Y is Y6 may be prepared from 3-chloro intermediate compounds LXXVIII and LXXIX respectively by treatment with pyrazole LXXX in the presence of an organic base as shown in Flow Diagram XXXIII.
FLOW DIAGRAM XXXIII
Figure imgf000056_0001
(LXXVIII) (LXXIX)
Figure imgf000056_0002
(XLIV, Y=Y^ (II, Y="5g)
Nitro intermediate compounds LXXVIII are prepared from acid intermediate LIU by conversion to disulfide LXXXI by sequential treatment with base, sodium sulfide, and acid as depicted in Flow Diagram XXXIV. Intermediate disulfide compound LXXXI is conver- ted to intermediate benxisothiazolone LXXXII by sequential treatment with thionyl chloride, bromine and ammonia, and this product then treated with phosphorous oxychloride in the presence of base.
FLOW DIAGRAM XXXIV
Figure imgf000057_0001
2. Ne_S.9ϊ_0 + Sk
3. HC1
Figure imgf000057_0002
1. S0C12
2. Br2 3. NH,
Figure imgf000057_0003
(LXXXII)
P0C13 N[(CH2)3CH3]3
Figure imgf000057_0004
(LXXVIII) Benzisothiazole and benzisozaxole intermediate compound LXxix is prepared as shown in Flow Diagram XXXV from nitro intermediate LXXVIII by reduction to amino intermediate LXXXIII under standard conditions such as iron in the presence of acid, followed by elaboration of the amino functionality to Q groups as described in u. S. 5,484,763, U. S. 5,523,278 and Flow Diagrams I-XIX. FLOW DIAGRAM XXXV
Figure imgf000058_0001
(LXXXIII)
U. S. 5,484,763 ϋ. S. 5,523,278
20 Flow Diagrams I-XIX
Figure imgf000058_0002
(LXXIX)
Compounds of formula I wherein Y is Y7 and Ys may be prepared as shown in Flow Diagram XXXVI by treatment of acid chloride inter-
™ mediate compound LXIX with organozinc reagent of formula LXXXIV to afford intermediate ketone compound LXXV, which is acylated with acid chloride LXXXVI in the presence of base to afford intermediate diketone of formula LXXXVII . Diketone LXXXVII is treated with hydrazine to afford a mixture of pyrazole regioiso-
35 mers LXXXVIII and LXXXIX, which is alkylated with an alkyl halide of formula XC to yield a mixture of regioisomeric pyrazoles which can be separated by column chromatography or fractional crystallization.
40
45 FLOW DIAGRAM XXXVI
Figure imgf000059_0001
(LXXXV)
Figure imgf000059_0002
(LXXXVI)
Figure imgf000059_0003
(LXXXVII)
NI^NH2
Figure imgf000059_0004
(LXXXIX)
R17Z1
(Z]_=C1, Br, I) (XC)
Figure imgf000059_0005
Figure imgf000059_0006
(I, Y=¥) (I, Y= ) Compounds of formula I wherein Y is Y9 may be prepared as shown in Flow Diagram XXXVII by bromination of intermediate ketone of formula LXXXV and subsequent treatment of bromoketone intermediate XCI with thioamide XCII.
FLOW DIAGRAM XXXVII
Figure imgf000060_0001
(LXXXV)
Figure imgf000060_0002
Compounds of formula I wherein Y is Yχo may be prepared as shown in Flow Diagram XXXVIII by reaction of acid chloride intermediate LXIX with amine compound XCII to afford intermediate amide XCIV, which on treatment with sodium hydride yields the compound of formula I wherein B=0. Alternatively, treatment of amide LXXVII with phoshoorous pentasulfide yields thioamide compound XCV, which on treatment with sodium hydride yields the compound wherein B=S. Treatment of amide XCIV with amine XCVI under dehydra¬ ting conditions affords compound I wherein B=NRι7. FLOW DIAGRAM XXXVIII
Figure imgf000061_0001
Compounds of formula I wherein Y is Yxx may be prepared as shown in Flow Diagram XXXIX by reaction of acid chloride LXIX with hydrazide XCVII to afford Intermediate hydrazide of formula XCVIII, which on treatment with phosphorous oxychloride and phosphorous pentasulfide yields compounds of formula I wherein B=0 and B=S respectively. FLOW DIAGRAM XXXIX
Figure imgf000062_0001
H2N HCOI^6 (XCVII)
Figure imgf000062_0002
(XCVIII)
Figure imgf000062_0003
(I, Y-Yχχ, B=O) (I, Y=Ylf B=S)
Treatment of acid chloride LXIX with amide XCIX affords amide intermediate C, which on treatment with hydrazine in the presence of acid yields triazole intermediate Cl . Alkylation of triazole intermediate Cl with alkyl halide XC affords compounds of formula I wherein Y=Yχχ and B=NRχ7 as shown in Flow Diagram XL. FLOW DIAGRAM XL
Figure imgf000063_0001
H^CC-R^ (XCIX)
Figure imgf000063_0002
Alternatively nitro intermediates XLIV wherein Y=Yχχ and B=0 and B=S can be prepared as depicted in Flow Diagram XLI by conversion of acid chloride CII to hydrazide intermediate CIII with hydrazide reagent XCVII and subsequent treatment with phosphorous oxychloride and phosphorous pentasulfide, respectively. FLOW DIAGRAM XLI
Figure imgf000064_0001
Hyfl HCOI^ (XCVII)
Figure imgf000064_0002
Acid chloride CIV may be prepared as outlined in Flow Diagram XLII. Treatment of thiophenol CIV with oxalyl chloride followed by aluminum chloride affords thiodione CV, which on treatment with ammonium hydroxide and hydrogen peroxide yields amide CVI. Basic hydrolysis of amide CVI affords acid CVII, which is nitrated under standard conditions to afford acid CVIII. Treatment of acid CVIII with thionyl chloride affords acid chloride CIV. FLOW DIAGRAM XLII
Figure imgf000065_0001
Compounds of formula I wherein Y is Y12 may be prepared as shown in Flow Diagram XLIII by treatment of intermediate LXXIX with hy- drazine to produce hydrazino intermediate CIX and subsequent treatment of this with amide CX.
FLOW DIAGRAM XLIII
Figure imgf000066_0001
(LXXIX)
H2NNH2
Figure imgf000066_0002
(I, Y=Yχ2)
Compounds of formula I wherein Y is Yχ3 may be prepared as shown in Flow Diagram XLIV by conversion of aldehyde LXXV to chloro intermediate CXI, and subsequent treatment of this intermediate with an olefin CXII in the presence oa a base such as triethyl- amine. FLOW DIAGRAM XLIV
Figure imgf000067_0001
l . B^NOH
2 . C--2 or NCS
Figure imgf000067_0002
(CXI )
Figure imgf000067_0003
( I , Y=Yι3) Compounds of formula I wherein Y is Yχ may be prepared by treatment of ketoester CXIII with sulfamide to afford intermediate of structural formula CXIV, and subsequent alkylation with alkyl halide XL as shown in Flow Diagram XLV.
FLOW DIAGRAM XLV
Figure imgf000068_0001
(I, Y=Y14) Intermediate ketoester CXII is prepared from chloro intermediate LXXVIII by treatment with cyanoacetic ester in the presence of base to afford intermediate cyanoester CXV which on treatment with acetyl chloride affords nitro ester CXVI . Reduction of nitro ester CVIII with iron in acetic acid affords amino ester CXVII which can be elaborated into an intermediate ester of formula CXVIII by the methods described in Flow Diagrams I-XIX. Oxidation of ester CXVIII with selenium dioxide affords ketoester CXIII as shown in Flow Diagram XLV. FLOW DIAGRAM XLVI
Figure imgf000069_0001
(LXXVIII)
C_ (CN)CQEt EtO-Na+
10
Figure imgf000069_0002
(CXVIII)
Figure imgf000069_0003
45
(CXIII) Compounds I wherein Y is Y5 and Y16 may be prepared as outlined in Flow Diagram XLVI by treatment of keto ester CXIII with amidine CXIX and amidine or guanidine CXX, respectively.
FLOW DIAGRAM XLVII
Figure imgf000070_0001
(CXIII)
Figure imgf000070_0002
Compounds XLIV wherein Y is Yχ7 and Yχ8 may be prepared as shown in Flow Diagram XLVIII. Acylation of ketone CXXI with ester CXXII in the presence of base affords intermediate keto ester CXXIII, which on treatment with hydrazine yields intermediate CXXIV, which can be alkylated with alkyl halide XL to afford compound XLIV wherein Y is Yχ . Oxidation of intermediate CXXIV with bromine yields intermediate CXXV which can be alkylated with alkyl halide XL to afford compound XLIV wherein Y is Yχ8- Ketone CXXI can be prepared from acid chloride CII using the method described in Flow Diagram XXXVI for the synthesis of ketoneLXXXIV. FLOW DIAGRAM XLVIII
Figure imgf000071_0001
20 (CXXIII)
Figure imgf000071_0002
Compounds XXV wherein Y is Yχ9 can be prepared as depicted in Flow Diagram XLIX by alkylation of ketone CXXI with alkyl halide CXXVI in the presence of base and subsequent hydrolysis to afford intermediate keto aldehyde CXXVII, which is treated with hydra- zine and oxidized as shown.
FLOW DIAGRAM XLIX
Figure imgf000072_0001
(CXXVII)
Figure imgf000072_0002
(XLIV, Y=J9)
Compounds XLIV wherein Y is Y2o may be prepared by treatment of the anion of ester CXVI with paraformaldehyde followed by oxidation of the hydroxy ester product to ester aldehyde CXXVIII as shown in Flow Diagram L. Treatment of ester aldehyde inter- mediate CXXVIII with amidine CXX in an inert solvent in the presence of base affords intermediate CXXIX, which can be alkylated with alkyl halide XL as shown.
FLOW DIAGRAM L
Figure imgf000073_0001
(CXVI)
1. LDA
2. (CH )n
3. [0]
Figure imgf000073_0002
(CXXVIII)
ent
Figure imgf000073_0003
Figure imgf000073_0004
(XLIV, Y= 0) Compounds wherein Y is Y2χ may be prepared as shown in Flow Diagram LI by treatment of chloro intermediate LXXVIII with malono- nitrile in the presence of base to afford intermediate dinitrile CXXX. Reduction of dinitrile CXXX affords dialdehyde CXXXI, which is treated with amidine CXX as shown.
FLOW DIAGRAM LI
Figure imgf000074_0001
(LXXVIII)
CH2 (CN)2 Et3N
Figure imgf000074_0002
(CXX)
Base
Inert solvent
Figure imgf000074_0003
(XLIV, Y=Y^) Compounds I wherein Y is Y22 and Y23 are prepared by treatment of keto ester CXIII with olefin CXXXII to afford intermediate CXXXIII, which is treated with phosphorous oxychloride or alkylated with alkyl halide LX as depicted in Flow diagram LII.
FLOW DIAGRAM LII
Figure imgf000075_0001
(CXIII )
(CXXXII )
Elevated
Temperature
Figure imgf000075_0003
CXXXIII
Figure imgf000075_0004
The syntheses of compounds wherein Y is Y24 through Y27 are de- picted in Flow Diagram LII. Coupling of acid chloride LXIX with organozinc reagent CXXXIV in the presence of a palladium catalyst affords ketone CXXXV, which on treatment with CXXXVI under dehy- dration conditions yields compounds I wherein Y is Y24. Compounds I wherein Y is Y24, B is 0, and B is sulfur can be oxidixed to compound I wherein Y is Y25- In similar fashion, intermediate ketone CXXXV can be reacted with intermediate CXXVII to afford compound I wherein Y is Y26 and this compound wherein B is O, and Bx is S can be oxidized to compound I wherein Y is Y27.
FLOW DIAGRAM LIU
Figure imgf000077_0001
Alternatively, compounds I wherein Y is Y24 and both B and B are oxygen can be prepared by treatment of dibromo intermediate LXXIII with diol CXXXVI in the presence of a silver salt such as silver trifluoromethanesulfonate as shown in Flow Diagram LIV.
FLOW DIAGRAM LIV
Figure imgf000078_0001
(I, Y=Y24,B=BI=0)
Compounds wherein Y is Y2g can be prepared by treatment of aldehyde LXXV with diol CXXXVIII in the presence of acid with azeotropic removal of water as shown in Flow Diagram LV.
FLOW DIAGRAM LV
Figure imgf000079_0001
p-TsOH "H20
Figure imgf000079_0002
(I, Y=Y28)
Compounds I wherein Y is Y29 and Y30 can be prepared by treatment of ketone CXXXV with hydroxy acids CXXXIX and CXL, respectively, under acidic conditions with azeotropic removal of water as shown in Flow Diagram LVI .
FLOW DIAGRAM LVI
Figure imgf000080_0001
(CXXXV)
Figure imgf000080_0002
( I , Y=Y29) ( I . Y=Y3θ)
Compounds wherein Y is Y3χ and Y33 can be prepared from keto ester CXLI by conversion to diol CXLIII by reduction for the case wherein Rχ5(X6) is hydrogen, or by reaction with organolithium reagent CXLII followed by reduction for the case wherein RXS( 6) is not hydrogen, and subsequent reaction of diol intermediate CXLIII with aldehyde CXLIV in the presence of acid, with azeotropic removal of water or by reaction with phosgene or thiophosgene as shown in Flow Diagram LVII.
FLOW DIAGRAM LVII
Figure imgf000081_0001
(CXLIII )
Figure imgf000081_0002
Keto ester CXXXII can be prepared from chloro intermediate LXXVIII using the procedure described in Flow Diagram XLV.
Compound XLIV wherein Y is Y32 and Y34 can be prepared from chloro intermediate LXXVIII by treatment with a dialkyl malonate in the presence of base to form diester CXLV, which can be alkylated with alkylating agent CXLVI to produce diester CXLVII. Diester CXLVII can be reduced to diol CXLVIII, which is treaed with aldehyde CXLIV in the presence of acid with azeotropic removal of water, or with phosgene or thiophosgene as depicted in Flow Diagram LVIII . FLOW DIAGRAM LVIII
Figure imgf000082_0001
(CXLVI II)
Figure imgf000082_0002
Compounds I wherein Y is Y35 may be prepared reaction of the anion of ester CXVIII with aldehyde CXLIV to generate diol intermediate CXLIX, which is treated with aldehyde CL in the presence of acid with azeotropic removal of water as depicted in Flow Diagram LIX.
FLOW DIAGRAM LIX
Figure imgf000083_0001
(CXVIII)
Figure imgf000083_0002
R 1.6 (15 £HO
(CL) TsOH or P205
Figure imgf000083_0003
(I, (Y="5§5)
Compounds I wherein Y is Y36 may be prepared reaction of the anion of methyl ketone CXXXV (R19=CH3) with aldehyde CXLIV, followed by reduction with agents such as sodium borohydride for the case wherein Rχ5{χ6) is hydrogen, or reaction with organolithium reagent CXLII for the case wherein Ri5(χ6) is not hydrogen, which affords diol intemediate CLI which is reacted with phosgene in the presence of a base as depicted in Flow Diagram LX. FLOW DIAGRAM LX
Figure imgf000084_0001
(CXXXV, Iχ.9=CH3)
n or
Figure imgf000084_0002
Figure imgf000084_0003
Et3N or Pyridine
Figure imgf000084_0004
Compounds I wherein Y is Y37 may be prepared by conversion of ester CXVIII to acid chloride CLII by sequential treatment with aqueous sodium hydroxide, N-chlorosuccinimide or N-bromosuccini - mide, and oxalyl chloride. Treatment of acid chloride CLII with reagent CLIII in the presence of base affords compound I wherein Y is Y37. FLOW DIAGRAM LXI
Figure imgf000085_0001
(CXVIII)
1. Aq. NaOH
2. NCS or NBS
3. (COCl^
Figure imgf000085_0002
Zχ=Cl, Br (CLII)
Figure imgf000085_0003
Compounds I wherein Y is Y38 may be prepared by conversion of diol CXLIII to halo intermediate CLIV and subsequent treatment with reagent CLV in the presence of a silver salt as depicted in Flow Diagram LXII . FLOW DIAGRAM LXII
(15)
Figure imgf000086_0001
(I, Y=Y38)
Compounds I wherein Y is Y39 and Y40 may be prepared by epoxidation of olefin CLVI and conversion of epoxide I (Y=Y39) to aziridine as depicted in Flow Diagram LXIII. FLOW DIAGRAM LXIII
Figure imgf000087_0001
1. NBS
10 HjO/dioxane
2. NaH or m-CPBA
15
Figure imgf000087_0002
35
40
45 The present invention also relates to intermediate compounds having the structural formula XLIV
Figure imgf000088_0001
wherein wherein X, Xx, Y and Z are as defined above for formula I .
Preferred intermediate compounds of formula XLIV are those whe rein Y is selected from
Figure imgf000088_0002
Y7 Ys Y9
Figure imgf000088_0003
Yio Yii Yl2
Figure imgf000089_0001
Yl6 Yl7 Yis
Figure imgf000089_0002
Figure imgf000089_0003
Figure imgf000089_0004
Y31 Y32 Y33
Figure imgf000090_0001
Y40 wherein
Ri5' R-18 R20 and R χ are each independently hydrogen, Cχ-C8 alkyl, Cχ-C8 haloalkyl, Cχ-C8 alkoxy, Cχ-C8 thioalkyl, halogen, nitro, cyano, hydroxy, C2-C6 alkenyl, C3-C6 alkynyl, C2-C6 haloalkenyl, C3-C8 cycloalkyl or R20 and the carbon on Y to which R 0 is attached may form an exocyclic double bond or when R2o and R χ are attached to the same carbon of Y 5, R o, R21 and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring;
Rχ6 is hydrogen, halogen, Cχ-C8 alkyl optionally substituted with C(0)R22, C02R 3, X2R24, S(0)malkyl, NR86R87, C -C8 haloalkyl, C(0)R25, C02R26, X3R27, CH=CHR28, C3-C8 cycloalkyl, N(R29)S02R30 or (subst.) phenyl;
When R 5 and Rχ6 are attached to separate adjacent carbons, as in Y24, they may form a six-membered heterocyclic or carbo- cyclic ring fused to the Y-ring;
Rχ7 is hydrogen, Cχ-C8 alkyl, C2-C8 alkenyl, C3-C6 alkynyl, C(0)R25, or (subst. ) benzyl ;
Ri9> R33 3 ' R35 R37 38 R39. R42/ 3 R44 6/ 47 R48 R50 51 R52' R53 55' R56 57 R60' Rθl δ2 64 65' 66 R69 70 7I' 73' 74 R75/ 76 R80 and R85 are each independently hydrogen, OH, Cχ-C8 alkyl, Cχ-C alkoxy,
C3-C8 cycloalkyl, C2-C8 alkenyl, C3-C6 alkynyl, (subst. ) benzyl or (subst.) phenyl; R23- R26 31 R40' R49 R58» R67. and R79 are each independently hy¬ drogen, Cχ-C8 alkyl, Cχ-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C5-C8 cycloalkenyl, Cs-C8 halocycloalkenyl, C3-C8 alkynyl, C3-C8 haloalkynyl, (subst. )benzyl, (subst.) phenyl, fur- furyl, pyridyl, thienyl, an alkali metal, alkaline earth metal, manganese, copper, zinc, cobalt, silver, nickel ammonium or organic ammonium cation;
R24. R27 and R28 are each independently hydrogen,
Cχ-Cχo alkyl optionally substituted with one to six halogens, one Cχ-C6 alkoxy group, C02R31, C(0)R32, C(OR33)2, C(SR34)2/ C(0)NR35R36, C(0)ON=CR37R38, cyano,
(subst.) phenyl or C(0)NHOR39; C2-Cχo alkenyl optionally substituted with one Cχ-C6 alkyl group, one to three halogens, one Cχ-C6 alkoxy group, CO2R40, C(0)R4χ,C(OR42)2, C(SR43)2, C(0)NR44R45,
Figure imgf000091_0001
cyano, (subst. ) phenyl or C(0)NHOR48;
C3-C8 cycloalkyl optionally substituted with one Cχ-C6 alkyl group, one to three halogens, one Cχ-C6 alkoxy group, CO2R49 C(O)R50,C(OR51)2, C(SR52)2/ C{0)NR53R54, C(0)0N=CR55R56, cyano, (subst .) phenyl or C(0)NHOR57; C5-C8 cycloalkenyl optionally substituted with one C-C6 alkyl group, one to three halogens, Cχ-C4 alkoxy group, C02R58, C(O)R59,C(OR60)2' C(SR6χ)2, C(0)NR62R63,
Figure imgf000091_0002
cyano, (subst. ) phenyl or C(0)NHOR66; C3-C8 alkynyl optionally substituted with one Cχ-C6 alkoxy group, C02R67, C (0)R68,C (OR69) 2. C(SR0)2, C (0)NR71R72,
C(0)ON=CR73R74, cyano, (subst. )phenyl or C(0)NHOR75; phenyl optionally substituted with one to three halogens, one to three Cχ-C6 alkyl groups, one to three Cχ-C6 alkoxy groups, one to three Cχ-C6 haloalkyl groups, one to three Cχ-C6 haloalkoxy groups, one cyano, one nitro, one NR76R77, one C(0)R8 or one C02R79.
R30 is OH, Cχ-C8 alkyl, C3-C8 cycloalkyl, Cχ-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C3-C8 alkynyl, (subst. )benzyl, (subst.) phenyl, or NR8oR8χ;
B and Bx are each independently oxygen, sulfur or NRχ ;
X2 and X3 are each independently 0 or S; and all optical isomers and diastereomers thereof.
More preferred formula XLIV intermediate compounds of this invention are those wherein
X is hydrogen or halogen,- Xx is hydrogen;
Z is sulfur of oxygen; Y is selected from Yx, Y2, Y3, Y4, Y5. e Yιo> Yn> Yi4» Yi5.
Yi6, Y22 Y24 Y25, Y26, 27 28 38» and Y39. Ri5# i8» 20' and R χ are each independently hydrogen, Cχ-C3 alkyl, Cχ-C3 haloalkyl, Cχ-C3 alkoxy, halogen, hydroxy or when R2o and R2χ are attached to the same carbon of Y25 an epoxide ring is formed; Rχ6 is hydrogen, halogen, Cχ-C3 alkyl optionally substituted with C(0)R22, C02R23, X2R24 or S(0)malkyl; phenyl; C -C3 haloalkyl, C(0)R25, C02R26, X3R27/ C3-C8 cycloalkyl, N(R29)SO2R30 or C2-C alkenyl;
Rχ7 is hydrogen, Cχ-C3 alkyl, C2-C4 alkenyl or C(0)R25; Ri9 R29 and R8o are each independently hydrogen or Cχ-C3 alkyl; 22 25 and R8χ are each independently hydrogen, Cχ-C3 alkyl, benzyl or (subst) phenyl ,- R23, R26 and R3χ are each independently hydrogen, Cχ-C3 alkyl, C2-C4 alkenyl, or C3-C6 alkynyl; R24 and R27 are each independently hydrogen or Cχ-C3 alkyl optionally substituted with one C02R3χ group or one Cχ-C3 alkoxy group; R30 Cχ-C3 alkyl, C3-C5 cycloalkyl, Cχ-C3 haloalkyl, C2-C4 alkenyl (subst.) benzyl, (subst. ) phenyl, or NR80R8χ; X2 and X3 are 0.
Most preferred compounds of formula XLIV are those wherein Y is taken from
Figure imgf000092_0001
Figure imgf000093_0001
i5 i8 20 and R21 are each independently hydrogen, Cχ-C3 alkyl, Cχ-C3 haloalkyl, Cχ-C3 alkoxy; Rχ6 is hydrogen, halogen, Cχ-C8 alkyl optionally substituted with X2 24; Cχ-C3 haloalkyl , phenyl or C2-C4 alkenyl;
R17 IS hydrogen, methyl or C(0)R2s;
R19 is hydrogen or Cχ-C3 alkyl;
R24 is hydrogen or Cχ-C3 alkyl; 25 is Cχ-C3 alkyl or phenyl; X2 is oxygen.
The present invention also relates to intermediate compounds ha- ving the structural formula II
Figure imgf000094_0001
( ID wherein wherein X, Xx, Y and Z are as defined above for formula I .
Preferred intermediate compounds of formula II are those wherein Y is selected from
Figure imgf000094_0002
Y7 Ys Y9
Figure imgf000094_0003
Figure imgf000095_0001
Figure imgf000096_0001
Y40 wherein
Ri5» Ri8. R20 and R2ι are each independently hydrogen, Cχ-C8 alkyl, Cχ-C8 haloalkyl, Cχ-C8 alkoxy, Cχ-C8 thioalkyl, halogen, nitro, cyano, hydroxy, C2-C6 alkenyl, C3-C6 alkynyl, C2-C6 haloalkenyl, C3-C8 cycloalkyl or R2o and the carbon on Y to which R20 is attached may form an exocyclic double bond or when R20 and R2X are attached to the same carbon of Y25, 20 R21 and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring;
Rχ6 is hydrogen, halogen, Cχ-C8 alkyl optionally substituted with C(0)R22, C02R23- 2 24 S(0)malkyl, NR86R87, Cχ-C8 haloalkyl, C(0)R25, C02R26, 3 27,
Figure imgf000096_0002
C3-C8 cycloalkyl, N(R29)SO2R30 or (subst.) phenyl ,-
When R 5 and Rχ6 are attached to separate adjacent carbons, as in Y24, they may form a six-membered heterocyclic or carbo- cyclic ring fused to the Y-ring;
Rχ7 is hydrogen, Cχ-C8 alkyl, C2~C8 alkenyl, C3-C6 alkynyl, C(0)R25, or (subst .) benzyl;
Rl9/ R29 33 34/ R35' R37' R38 R39' R42' R43 R44 R46 R47 48' 50 R51 R52 R53 R55 R56 R57' RδO R-61/ R62 δ » R65'
R66 R69 R70/ 71 R73 R74 R75. 76 RδO and R85 are each independently hydrogen, OH, Cχ-C8 alkyl, Cχ-C4 alkoxy, C3-C8 cycloalkyl, C2-C8 alkenyl, C3-C6 alkynyl, (subst.) benzyl or (subst.) phenyl; R23, R26 R31 R40 R49' R58' δ7 and R79 are each independently hydrogen, Cχ-C8 alkyl, Cχ-C8 haloalkyl, C3-C8 cycloalkyl, C -C8 halocycloalkyl, C2~C8 alkenyl, C2-C8 haloalkenyl, C5-C8 cycloalkenyl, C5-C8 halocycloalkenyl, C3-C8 alkynyl, C3-C8 haloalkynyl, (subst. ) benzyl, (subst.) phenyl, fur- furyl, pyridyl, thienyl, an alkali metal, alkaline earth metal, manganese, copper, zinc, cobalt, silver, nickel ammonium or organic ammonium cation; R24. 27» and R28 are each independently hydrogen,
Cχ-C10 alkyl optionally substituted with one to six halogens, one Cχ-C6 alkoxy group, C02R3ι, C(0)R32, C(OR33)2, C(SR34)2, C(0)NR35R36, C(0)ON=CR37R38, cyano, (subst.) phenyl or C(0)NHOR39;
C -Cχ0 alkenyl optionally substituted with one Cχ-C6 alkyl group, one to three halogens, one Cχ-C6 alkoxy group, CO2R40 C(0)R4ι,C(OR42)2/ C(SR43)2/ C(0)NR44R45, C(0)0N=CR46R47, cyano, (subst. ) phenyl or C(0)NH0R48; C3-C8 cycloalkyl optionally substituted with one Cχ-C6 alkyl group, one to three halogens, one Cχ-C6 alkoxy group, CO2R49, C(0)R5o,C(OR5χ)2, C(SR5 )2 C(0)NR53R54, C(0)ON=CR55R56, cyano, (subst. ) phenyl or C(0)NHOR57; C5~C8 cycloalkenyl optionally substituted with one Cχ-C6 alkyl group, one to three halogens, Cχ-C4 alkoxy group,
C02R58, C(O)R59,C(OR60)2, C(SR6χ)2/ C(0)NR62R63 C(0)ON=CR64R65, cyano, (subst. ) phenyl or C(0)NHOR66. C3-C8 alkynyl optionally substituted with one C -Cδ alkoxy group, C02R67/ C (0)R68,C (OR69) 2, C(SR70)2/ C(0)NR7χR72, C(0)ON=CR73R74, cyano, (subst. ) phenyl or C(0)NHOR75;
phenyl optionally substituted with one to three halogens, one to three Cχ-C6 alkyl groups, one to three Cχ-C6 alkoxy groups, one to three Cχ-C6 haloalkyl groups, one to three Cχ-C6 halo- alkoxy groups, one cyano, one nitro, one NR76R7, one C(0)R8 or one C02R79;
R30 is OH, Cχ-C8 alkyl, C3-C8 cycloalkyl, Cχ-C8 haloalkyl, C2-C8 alkenyl, C2~C8 haloalkenyl, C3-C8 alkynyl, (subst. ) benzyl, (subst.) phenyl, or NR8oR8ι;
B and Bx are each independently oxygen, sulfur or NRχ7;
X and X3 are each independently 0 or S; and all optical isomers and diastereomers- thereof.
More preferred formula II intermediate compounds of this invention are those wherein
X is hydrogen or halogen; Xx is hydrogen; Z is sulfur of oxygen.
Y is selected from Yx, Y2, Y3, Y4, Y5, Y6 , Y10, Yxx, Y14, Yχ5 Yi6. Y2 Y2 Y25 Y26. Y27 Y28, Y38- and Y39. i5 R18 R 20 and R2X are each independently hydrogen, Cχ-C3 alkyl,
Cχ-C3 haloalkyl, Cχ-C3 alkoxy, halogen, hydroxy or when
R2o and R2X are attached to the same carbon of Y25 an epoxide ring is formed; Rχ6 is hydrogen, halogen, Cχ-C3 alkyl optionally substituted with C(0)R22, C02R23 X2R24/ or S(0)malkyl; phenyl; C -C3 haloalkyl, C(0)R25, C02 26# X3R27 C3-C8 cycloalkyl,
N(R29)S02R3o or C2-C4 alkenyl; Rχ7 is hydrogen, Cχ-C3 alkyl, C2-C4 alkenyl or C(0)R25,- R23, R26 and R3χ are each independently hydrogen, Cχ-C3 alkyl,
C2-C4 alkenyl, or C3-C6 alkynyl; R22 R 5 and Rsi are each independently hydrogen, Cχ-C3 alkyl, benzyl or (subst) phenyl; R24 and R27 are each independently hydrogen or Cχ-C3 alkyl optio - nally substituted with one C02R3χ group or one Cι-C alkoxy group; Rχ9, R29 and Rδo are each independently hydrogen or Cχ-C alkyl; R30 Cχ-C3 alkyl, C3-C5 cycloalkyl, Cχ-C3 haloalkyl, C2-C4 alkenyl
(subst .) benzyl, (subst. ) phenyl, or NR8oR8χ; X2 and X3 are O.
Most preferred compounds of formula II are those wherein
Z is sulfur ; Y is taken from
Figure imgf000098_0001
Figure imgf000099_0001
Rl5 i8 R20 and R2X are each independently hydrogen, Cχ-C3 alkyl,
Cχ-C3 haloalkyl, Cχ-C alkoxy; Rχ6 is hydrogen, halogen, Cχ-C8 alkyl optionally substituted with X2R24; Cχ-C3 haloalkyl, phenyl or C2-C4 alkenyl; Rχ is hydrogen, methyl or C(0)R25; R24 is hydrogen or Cχ-C alkyl; R25 is Cχ-C alkyl or phenyl; Rχ9 is hydrogen or Cχ-C3 alkyl;
X2 is oxygen .
The present invention also relates to intermediate compounds of having the structural formula XL
Figure imgf000100_0001
(XL) wherein Rχ# R2, X, Xx Y and Z are as defined above for formula I.
Preferred compounds of formula XL are those where Y is selected from
Figure imgf000100_0002
Yi Y2 Y3
Figure imgf000100_0003
Y7 Ys Y9
Figure imgf000101_0001
Y28 Y29 Y30
Figure imgf000102_0001
Y40 wherein i5 Ri8 R20 and R are each independently hydrogen, Cχ-C8 alkyl, Cχ-C8 haloalkyl, Cχ-C8 alkoxy, Cχ-C8 thioalkyl, halogen, nitro, cyano, hydroxy, C2-C6 alkenyl, C3-C6 alkynyl, C2-C6 haloalkenyl, C3-C8 cycloalkyl or R20 and the carbon on Y to which R2o is attached may form an exocyclic double bond or when R2o and R2X are attached to the same carbon of Y25, 20 R2χ and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring;
Rχ6 is hydrogen, halogen, Cχ-C8 alkyl optionally substituted with C(0)R22, C02R23 X2 24 S(0)malkyl, NR86R87, Cχ-C8 haloalkyl, C(0)R25. C02R26, X3 27 CH=CHR28, C3-C8 cycloalkyl, N(R29)SO2R30 or (subst.) phenyl ;
When Rχ5 and Rχ6 are attached to separate adjacent carbons, as in Y24, they may form a six-membered heterocyclic or carbocyclic ring fused to the Y-ring;
Rχ7 is hydrogen, Cχ-C8 alkyl, C2-C8 alkenyl, C3-C6 alkynyl, C(0)R25, or (subst. ) benzyl; Rl9# 29 R33' R34 R35 37 38 R39 R42/ R43' R44/ R46 R47 48 R50 R51 R52 R53/ R55 R56/ 57» R60 Rδl/ R62 R64 β5 / Rδ6 / 69 R70 R71 R?3» R74 R75» R76/ Rβo and R85 are each independently hydrogen, OH, Cχ-C8 alkyl, Cχ-C4 alkoxy, C3-C8 cyclo- alkyl, C2-C8 alkenyl, C3-C6 alkynyl, (subst.) benzyl or (subst.) phenyl; R23 R26» R31 R40 R49# R58 67# and R9 are each independently hydrogen, Cχ-C8 alkyl, Cχ-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl , C2-C8 alkenyl, C2-C8 haloalkenyl, C5-C8 cyclo- alkenyl, C5-C8 halocycloalkenyl, C3-C8 alkynyl, C3-C8 haloal- kynyl, (subst. ) benzyl, (subst.) phenyl, furfuryl, pyridyl, thienyl, an alkali metal, alkaline earth metal, manganese, copper, zinc, cobalt, silver, nickel ammonium or organic ammonium cation; R24, R27, and R28 are each independently hydrogen,
Cχ-Cχo alkyl optionally substituted with one to six halogens, one Cχ-C6 alkoxy group, C02R3χ, C(0)R32, C(OR33)2, C(SR34)2, C(0)NR35R36, C(0)ON=CR37R38, cyano, (subst.) phenyl or C(0)NHOR39; C2-Cχo alkenyl optionally substituted with one Cχ-C6 alkyl group, one to three halogens, one Cχ-C6 alkoxy group, CO2R40, C(0)R41,C(OR2)2/ C(SR3)2. C(0)NR44R45, C(0)ON=CR46R7, cyano, (subst .) phenyl or C(0)NHOR48; C3-C8 cycloalkyl optionally substituted with one Cχ-C6 alkyl group, one to three halogens, one Cχ-C6 alkoxy group,
C02R49, C(0)R5o,C(OR5χ)2, C(SR52)2/ C(0)NR53R54, C (0)ON=CR55R56, cyano, (subst .) phenyl or C (0)NHORs ; C5-C8 cycloalkenyl optionally substituted with one Cχ-C6 alkyl group, one to three halogens, Cχ-C4 alkoxy group, C02R58, C(O)R59,C(OR60)2, C(SR6χ)2, C(0)NR62R63,
C (0)ON=CR64RS5, cyano, (subs .) henyl or C(0)NHOR66; C3-C8 alkynyl optionally substituted with one Cχ-C6 alkoxy group, C02R67 C (0) R68,C (OR69) 2, C(SR70)2 C (0) NR71R72, C(0)ON=CR73R74, cyano, (subst. ) phenyl or C(0)NHOR75;
phenyl optionally substituted with one to three halogens, one to three Cχ-C6 alkyl groups, one to three Cχ-C6 alkoxy groups, one to three Cχ-C6 haloalkyl groups, one to three Cχ-C6 halo- alkoxy groups, one cyano, one nitro, one NR76R77, one C(0)R 8 or one C02R9;
R30 is OH, C -C8 alkyl, C3-C8 cycloalkyl, Cχ-C8 haloalkyl, C2-C8 alkenyl, C2~C8 haloalkenyl, C3-C8 alkynyl, (subst. ) benzyl, (subst.) phenyl, or NR80R8χ; B and Bx are each independently oxygen, sulfur or NRχ ; X2 and X3 are each independently O or S;
and all optical isomers and diastereomers thereof. More preferred compounds of formula XL are those wherein
R is Cχ-C3 haloalkyl; X is hydrogen or halogen; x is hydrogen; Z is sulfur; Y is selected from Ylf Y2, Y3 Y4, ϊs# Ye, Yιo# Yii. Yi4. l5 Yie, 22, 24, Y25 26 Y 7 Y28 Y38, and Y39. Ri5# R-18 R20 and R ι are each independently hydrogen, Cχ-C8 alkyl, Cχ-C8 haloalkyl, Cχ-C8 alkoxy, Cχ-C8 thioalkyl, halogen, nitro, cyano, hydroxy, C2-C6 alkenyl, C3-C6 alkynyl, C2-C6 haloalkenyl, C3-C8 cycloalkyl or R o and the carbon on Y to which R2o is attached may form an exocyclic double bond or when R20 and R2χ are attached to the same carbon of Y25, R20/ R21 and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring; Rχ6 is hydrogen, halogen, Cχ-C8 alkyl optionally substituted with C(0)R22, C02R23, 2 4 S(0)malkyl, NR86R87, Cχ-C8 haloalkyl, C(0)R25, C02R26, X3R27, CH=CHR28, C3-C8 cycloalkyl, N(R29)S02R3o or (subst.) phenyl;
When Rχ5 and Rχ6 are attached to separate adjacent carbons, as in Y24, they may form a six-membered heterocyclic or carbocyclic ring fused to the Y-ring; Rχ7 is hydrogen, Cχ-C8 alkyl, C2-C8 alkenyl, C3-C6 alkynyl, C(0)R25, or (subst. ) benzyl ; l9 9' 33 R34» R35/ 37 38 R39 42 43' R44' 46/ 47 8 R50' 51 R52 R53# R55/ R56 R57/ R60 δl' R62/ R64/ R65
Rδ6/ 69 R7o» R71. R73 R74/ 75 R76/ βo/ and R85 are each independently hydrogen, OH, Cχ-C8 alkyl, Cχ-C4 alkoxy, C3-C8 cycloalkyl, C2-C8 alkenyl, C3-C6 alkynyl, (subst.) benzyl or (subst.) phenyl; R23' R 6 R3i R40/ R 9 R58, R67 and R 9 are each independently hydrogen, Cχ-C8 alkyl, Cχ-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C2~C8 alkenyl, C2-Cs haloalkenyl, C5-C8 cycloalkenyl, Cs-C8 halocycloalkenyl, C3-Cs alkynyl,
C3-C8 haloalkynyl, (subst. ) benzyl, (subst.) phenyl, fur- furyl, pyridyl, thienyl, an alkali metal, alkaline earth metal, manganese, copper, zinc, cobalt, silver, nickel ammonium or organic ammonium cation; R24, R 7, and R28 are each independently hydrogen,
Cχ-Cχ0 alkyl optionally substituted with one to six halogens, one Cχ-C6 alkoxy group, C02R3χ, C(0)R32, C(OR33)2, C(SR34)2, C(0)NR35R36, C(0)0N=CR37R38, cyano, (subst.) phenyl or C(0)NH0R39; c 2 -cιo alkenyl optionally substituted with one Cχ-C6 alkyl group, one to three halogens, one Cχ-C6 alkoxy group, C02R40, C(0)R4χ,C(OR42)2, C(SR43)2, C(0) R44R45, C(0)ON=CR 6R47, cyano, (subst. ) phenyl or C (0)NHOR48;
C3-C8 cycloalkyl optionally substituted with one Cχ-Cβ alkyl group, one to three halogens, one Cχ-C6 alkoxy group, C02R49, C(0)R5o,C(OR5χ)2, C(SR52)2, C(0)NR53R54, C(0)0N=CR55R56, cyano, (subst. ) phenyl or C(0)NHOR57;
C5-C8 cycloalkenyl optionally substituted with one Cχ-C6 alkyl group, one to three halogens, Cχ-C4 alkoxy group, C02R58, C(0)R59,C(OR6o)2, C(SR61)2, C(0)NR62R63,
Figure imgf000105_0001
cyano, (subst. ) phenyl or C(0)NHOR6e;
C3-C8 alkynyl optionally substituted with one Cχ-C6 alkoxy group, C02R67, C (0)R68,C (OR69) 2. C(SR70)2* C(0)NR71R72, C(0)0N=CR73R7 , cyano, (subst. ) phenyl or C(0)NHOR75;
phenyl optionally substituted with one to three halogens, one to three Cχ-C6 alkyl groups, one to three C -Cδ alkoxy groups, one to three Cχ-C6 haloalkyl groups, one to three C-Cβ halo- alkoxy groups, one cyano, one nitro, one NR6R77, one C(0)R8 or one C02R9;
R3o is OH, Cχ-C8 alkyl, C3-C8 cycloalkyl, Cχ-C8 haloalkyl, C2-C8 alkenyl, C2~C8 haloalkenyl, C3-C8 alkynyl, (subst. )benzyl, (subst.) phenyl, or NRSQRSI;
B and Bx are each independently oxygen, sulfur or NRχ ;
X2 and X3 are each independently O or S; and all optical isomers and diastereomers thereof.
Most preferred compounds of formula XL are those wherein R2 is triflurormethyl; Z is sulfur; Y is taken from
Figure imgf000105_0002
Figure imgf000106_0001
Figure imgf000107_0001
R15. Ri8 R 0 and R2X are each independently hydrogen, Cχ-C3 alkyl , Cχ-C3 haloalkyl , Cχ-C3 alkoxy;
Rχ6 is hydrogen, halogen, Cχ-C8 alkyl optionally substituted with X2R24 Cχ-C3 haloalkyl , phenyl or C2-C4 alkenyl ;
Rχ7 is hydrogen, methyl or C (0) R 5 ;
R24 is hydrogen or Cχ-C3 alkyl ;
R25 is Cχ-C3 alkyl or phenyl ;
Rχ9 is hydrogen or Cχ-C3 alkyl ; X is oxygen.
The present invention also relates to intermediate compounds of having the structural formula CXIII
Figure imgf000107_0002
wherein Q, X, x, and Z are defined as above for formula I.
Preferred compounds of formula CXIII are those wherein
Q is Q7 or Q24;
R is Cχ-C6 alkyl, C2-C6 alkenyl, C3-C6 alkynyl or NH2;
R2 is Cχ-C6 alkyl or Cχ-C6 haloalkyl;
R3 is hydrogen;
More preferred compounds of formula CXIII are those wherein
Q is Q24;
R is Cχ-C3 alkyl;
R2 is Cχ-C3 haloalkyl;
Z is sulfur;
X is hydrogen or halogen;
X is hydrogen; Most preferred compounds of formula CXIII are those wherein Q is
Figure imgf000108_0001
Z is sulfur; X2 is oxygen.
In order to facilitate a further understanding of the invention, the following examples are presented to illustrate more specific details thereof. The invention is not to be limited thereby except as defined in the claims.
EXAMPLE 1
Preparation of 2-Chloro-4-fluoro-5-nitrobenzoyl chloride
Figure imgf000109_0001
A mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (50.0 g, 0.228 mol) and N,N-dimethylformamide (5 drops) in 1, 2-dichloroethane is treated dropwise with oxalyl chloride (30.8 mL, 0.353 mol), re- fluxed for 3 hours, cooled, and concentrated in vacuo to obtain the title product as an orange solid which is identified by NMR spectral analyses .
EXAMPLE 2
Preparation of 2-Cchloro-5-nitrophenyl l-methylpyrrol-2-yl ketone
Figure imgf000109_0002
To a mixture of n-butyllithium (2.5 M in hexanes, 100 ml, 0.250 mol) and tetrahydrofuran at room temperature is added N-methyl- pyrrole (40.6 g, 0.500 mol) dropwise over 30 minutes. The resultant mixture is stirred 90 minutes at 35-40°C and cooled to -70°C. Zinc chloride (0.5 M in tetrahydrofuran, 500 ml, 0.25 mol) is ad- ded dropwise such that the temperature does not exceed -60°C. The resultant mixture is allowed to warm to 0°C and stirred one hour at 0°C. A solution of 2-chloro-5-nitrobenzoyl chloride (60.5 g, 0.275 mol) in tetrahydrofuran is added, followed by tetrakis-tri- phenylphosphine palladium (5.00 g) . The resultant mixture is al- lowed to warm to room temperature, stirred overnight, and quenched with 10% aqueous hydrochloric acid. The organic layer is saved and the aqueous layer is extracted with ethyl acetate. The organic layers are combined, washed with saturated sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. Concentration in vacuo affords a maroon gum, which is chromato- graphed on silica gel with hexanes-ethyl acetate to afford the title compound as a yellow solid (12.7 g, 19.2%, mp 108.5-109.5 °C) which is identified by IR and NMR spectral analysis.
Using an essentially identical procedure and the appropriate he- terocycle the following ketones are prepared:
Figure imgf000110_0001
mp (°C)
75-77
Figure imgf000110_0002
mp (°C)
Figure imgf000111_0001
EXAMPLE 3
Preparation of 3- (l-Methylpyrrol-2-yl) -5-nitro-l, 2-benziso- thiazole
Figure imgf000111_0002
To a mixture of 2-chloro-5-nitrophenyl l-methylpyrrol-2-yl ketone (7.00 g, 26.4 mmol) and dimethyIformamide is added sulfur (0.850 g, 26.6 mmol) followed by ammonium hydroxide (25.0 ml). The resultant mixture is stirred two hours at 70-80°C and overnight at ambient temperature. The mixture is poured into water and vacuum filtered. The resultant red solid is taken up in methylene chloride and chromatographed on silica gel with hexanes- methylene chloride to afford the title compound as an orange solid, identified by NMR spectral analysis.
Using essentially the same procedure on the appropriate ketones, the following products are obtained:
Figure imgf000111_0003
Y mp (QC. o-
■Ό 174-175
Figure imgf000112_0001
Y mp (°C)
Figure imgf000113_0001
EXAMPLE 4
Preparation of 5-Amino-3- (l-methylpyrrol-2-yl) -1, 2-benziso- thiazole
Figure imgf000114_0001
To a mixture of 3- (l-methylpyrrol-2-yl) -5-nitro-l, 2-benziso- thiazole (1.5 g, 5.79 mmol), ethyl acetate and ethanol is added tin(II) chloride dihydrate (6.5 g, 28.8 mmol). The resultant mixture is heated to reflux, stirred 30 min at reflux and cooled to room temperature. The mixture is diluted with ethyl acetate and slowly quenched with solid sodium bicarbonate and water. Brine is added and the resultant mixture stirred and allowed to stand until layer separation is complete. The organic layer is saved and the aqueous layer is extracted with ethyl acetate. The solids which form in the aqueous layer are triturated with ethyl acetate, filtered and the filtrate combined with the above organic layers. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a brown oil (1.10 g, 84.6%) identified by NMR spectral analysis.
Using essentially the same procedure on the appropriate 5-nitro-3-heterocyclic benzisothiazole, the following compound is obtained:
Figure imgf000114_0002
mp (°C)
CH,
Figure imgf000114_0003
EXAMPLE 5
Preparation of 3- [3- (l-Methylpyrrol-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
Figure imgf000115_0001
Figure imgf000115_0002
To a mixture of 5-amino-3- (l-methylpyrrol-2-yl) -1, 2-benziso- thiazole (1.05 g, 4.59 mmol) and acetic acid is added CL 356698 (0.960 g, 4.60 mmol). The resultant mixture is stirred at reflux for two hours, cooled to room temperature, diluted with ice water and stirred vigorously for approximately 15 minutes. Filtration and drying affords the title compound as a gray solid (1.50 g, 83.3%, mp 125-130°C) which is identified by NMR spectral analysis.
Using essentially the same procedure with the appropriate amin- obenzisothiazoles , the following products are obtained:
Figure imgf000116_0001
X 0 mp (°C)
- H >250
Figure imgf000116_0002
5
H
Figure imgf000116_0003
mp (QC)
Figure imgf000117_0001
X mp (°C)
Figure imgf000118_0001
EXAMPLE 6
Preparation of l-Methyl-3- [3- (l-methylpyrrol-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) racil
Figure imgf000119_0001
To a mixture of 3- [3- (l-methylpyrrol-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil (1.35 g, 3.44 mmol), dry dimethyIformamide and potassium carbonate (0.710 g, 5.14 mmol) is added iodomethane (0.730 g, 5.14 mmol). The resultant mixture is stirred overnight at room temperature and poured into ice water. Filtration and drying affords the title compound as a pink foam (0.300 g, 21.4%) which is identified by NMR spectral analysis.
Using essentially the same procedure on the appropriate uracil- substituted benzisothiazoles the following compounds are obtained:
Figure imgf000120_0001
p (°C)
Figure imgf000120_0002
X mp (°C)
Figure imgf000121_0001
mp (°C)
Figure imgf000122_0001
3 30 0 ~i N— > N-CH H
^0 -CH3
N— N H
35
0
5 EXAMPLE 7
Preparation 2-Chloro-5-nitrophenyl 2-furyl ketone
Figure imgf000123_0001
To a mixture of 2, chloro-5-nitrobenzoyl chloride (5.50 g, 0.0250 mol) and tetrahydrofuran is added 2-tributylstannylfuran (10.1 g, 0.0275 mol) followed by dichloro-bis-triphenylphosphine palladium (0.540 g, 0.00075 mol). The resultant mixture is stirred overnight at room temperature and concentrated in vacuo. The resultant oil is chroma ographed on silica gel with methylene chlo- ride-hexanes to afford the title compound as a bright yellow solid (4.95 g, 78.7%, mp 93-96°C)which is identified by IR and NMR spectral analysis.
EXAMPLE 8
Preparation of 2-cChloro-5-nitrophenyl 3-chloro-2-thienyl ketone
Figure imgf000123_0002
To a mixture of aluminum chloride (1.33 g, 0.0102 mol) and methylene chloride is added 3-chlorothiophene (1.21 g, 0.0102 mol) dropwise. The resultant mixture is stirred 30 minutes and treated with a solution of 2.chloro-5-nitrobenzoyl chloride (2.20 g, 0.0100 mol) in methylene chloride. The resultant mixture is stirred overnight at room temperature, poured into ice, acidified with concentrated hydrochloric acid and extracted twice with methylene chloride. The combined organic layers are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a brown oil. Trituration with ether affords the title compound as a brown solid (1.33 g, 44.0%, mp 114-116°C) which is identified by NMR spectral analysis.
In essentially the same manner, treatment of 2-chloro-5-nitroben- zoyl chloride with 2, 5-dimethylthiophene affords the following compound:
Figure imgf000124_0001
EXAMPLE 9
Preparation of 2-Chloro-5-nitrophenyl 5-methyl-2-thienyl ketone
Figure imgf000124_0002
To a mixture of 2-chloro-5-nitrobenzoic acid )40.4 g, 0.200 mol), 2-methylthiophene (20.0 g, 0,200 mol) and methylene chlolride is added phosphorous pentoxide (142 g, 1.00 mol). The resultant mixture is stirred overnight at room temperature and quenched with dropwise addition of water. The organic layer is saved and the aqueous layer is extracted with methylene chloride. The combined organic layers are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with methylene chloride to afford the title compound as a solid (26.6 g. 47.6%, mp 68-69°C) which was identified by IR and NMR spectral analysis.
Using essentially the same procedure with 2-chloro-5-nitrobenzoic acid and 3 ,4-dimethylthiophene, the following compound is obtai- ned (mp 100-103 °C) :
Figure imgf000125_0001
EXAMPLE 10
Preparation of 5-Amino-3- (3-chloro-2-thienyl) -1, 2-benzisothiazole
Figure imgf000125_0002
To a mixture of 3- (5-chloro-2-thienyl) -5-nitrobenzisothiazole (5.67 g, 0.0191 mol), ethyl acetate and glacial acetic acid at 70°C is added iron powder (5.50 g, 0.0955 mol) portion-wise. The resultant mixture is stirred overnight at 70°C and filtered after cooling with ethyl acetate wash. The organic layer is washed with three portions of water and one of brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel with methylene chloride-diethyl ether affords a yellow foam, which is recrystallized from ether to afford the title compound as a yellow solid (3.13 g, 61.5%, mp 128-132°C) , which is identified by NMR and IR spectral analysis.
In essentially the same manner the appropriate nitrobenzothiazo- les afford the following compounds :
Figure imgf000126_0001
mp (°C)
Figure imgf000126_0002
102-104
108-110
CH ό,
Figure imgf000126_0003
mp (°C)
Figure imgf000127_0001
-CH,
\
N— N
Figure imgf000127_0002
EXAMPLE 11
Preparation of N- [3- (3-Methoxy-2-thienyl) -1, 2-benziso- thiazol-5-yl] -1-cyclohexene-l, 2-dicarboximide
Figure imgf000128_0001
A mixture of 3- (5-methoxy-3-thienyl) -5-aminobenzisothiazole (0.440 g, 1.68 mmol), tetrahydrophthalic anhydride (0.280 g, 1.84 mmol) and acetic acid is stirred three hours at reflux, cooled to room temperature and allowed to stand overnight. The resultant suspension is filtered to afford the title compound as yellow crystals (0.550 g, 82.6%, mp 146-149°C) fwhich is identified by IR and NMR spectral analysis.
Using essentially the same procedure and the appropriate amine the following compounds are obtained:
Figure imgf000128_0002
X mp (°C)
Figure imgf000129_0001
EXAMPLE 12
Preparation of 3- [3- (3-Hydroxy-2-thienyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000129_0002
To a mixture of 3- [3- (3-methoxy-2-thienyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil (0.500 g, 1.14 mmol) and methylene chloride at -5°C is added boron trichloride (IM in methylene chloride, 2.30 ml, 2.3 mmol) via syringe. The resultant mixture is stirred two hours at -5°C, warmed to room temperature, stirred overnight and poured into cold 10% hydrochloric acid. The mixture is extracted with methylene chloride. The organic layer is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to an oil. The oil is crystallized in ether to afford the title compound as pale yellow-green crystals (0.350 g, 72.2%) which is characterized by NMR spectral analysis. EXAMPLE 13
Preparation of Methyl [ (2- [5- [3, 6-dihydro-3-methyl-2, 6- dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benziso- thiazol-3-yl] -3-thienyl] oxy] acetate
Figure imgf000130_0001
To a mixture of 3- [3- (3-hydroxy-2-thienyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil (0.580 g, 1.36 mmol) in dimethylformamide ,is added potassium carbonate (0.230 g, 1.66 mmol) . The resultant mixture is dtirred 30 minutes and treated with methyl bromoacetate (0.230 g, 1.50mmol) . The mixture is stirred over a weekend at room temperature and poured into water. Filtration and drying affords the title compound as an off-white solid (0.550 g, 81.4%, mp 73-79°C) which is identified by NMR spectral analysis.
In an essentially identical manner treatment of CL 1008743 with the appropriate alkylating agents gives the following compounds:
Figure imgf000130_0002
mp (°C)
Figure imgf000131_0001
EXAMPLE 14
Preparation of 3- [3- [3- (Bromomethl) -2-thienyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000131_0002
To a mixture of 3- [3- [3- (methyl) -2-thienyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) racil (0.420 g, 0.993 mmol) and carbon tetrachloride is added N-bromosuccinimide (0.200 g, 1.12 mmol) and benzoyl peroxide (10.0 mg) . The resultant mixture is stirred overnight at reflux, cooled and filtered. The filtrate is concentrated in vacuo and the residue partitioned between water and methylene chloride. The organic layer is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with methylene chloride-diethyl ether to afford a pale yellow oil, which is crystallized in diethyl ether to afford the title compound as a cream-colored olid (0.340 g, 68.1%, mp 169oC (dec) )which is identified by NMR spectral analysis. EXAMPLE 15
Preparation of 3- [3- [3- (Methoxymethyl) -2-thienyl] -1,2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000132_0001
To a mixture of 3- [3- [3- (bromomethl) -2-thienyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil (1.00 g, 1.99 mmol) , methylene chloride and methanol is added silver trifluror- methylsulfonate. The resultant white suspension is stirred overnight at room temperature and filtered through a pad of Ce- lite (registered trademark?) with methylene chloride wash. The filtrate is washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a pale yellow solid, which is recrystallized from diethyl ether to afford the title compound (0.790 g, 87.7%, mp 131-133°C) which is identified by NMR spectral analysis.
EXAMPLE 16
Preparation of 3- [3- [3- (Hydroxymethyl) -2-thienyl] -1,2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000133_0001
To a mixture of 3- [3- [3- (bromomethl) -2-thienyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil (0.840 g, 1.67 mmol) , dimethylsulfoxide and sodium nitrite is added glacial ace- tic acid. The resultant mixture is stirred overnight at 50°C, cooled and acidified with 10% aqueous hydrochloric acid. The mixture is diluted with water and extracted twice with ethyl acetate. The combined organic layers are washed with saturated sodium carbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with diethyl ether-methylene chloride to afford the title compound as an off-white solid (0.290 g, 38.3%, mp 168-169°C) which is identified by IR and NMR spectral analysis.
EXAMPLE 17
Preparation of o-Chlorophenyl 3-pyridyl ketone
Figure imgf000133_0002
To a mixture of n-butyllithium (1.7 M in hexanes, 100 ml, 0.170 mol) and diethyl ether at -78°C under an inert atmosphere is added a solution of 3-bromopyridine (24.0 g, 0.152 mol) in diethyl ether dropwise, followed by dropwise addition of a solution of 2-chlorobenzonitrile (20.7 g, 0.151 mol) in diethyl ether. The resultant mixture is stirred at -78°C for one hour, warmed to room temperature and diluted with hydrochloric acid (1.9 N, 300 ml). The organic layer I extracted with 3N hydrochloric acid. The acidic aqueous layers are combined, stirred one hour at reflux and cooled to room temeperature. The mixture is basified with 5% aqueous sodium hydroxide and extracted with diethyl ether. The organic layer is concentrated in vacuo and the residue is chromatographed on silica gel to provide the title compound as a yellow oil (22.3 g, 68.0%) which is identified by NMR spectral analysis.
Using essentially the same procedure with 2-chlorobenzonitrile and the appropriate bromopyridine the following compounds are ob- tained:
Figure imgf000134_0001
mp (°C)
Figure imgf000134_0002
EXAMPLE 18
Prepatarion of 3- (2-Chloro-5-nitrobenzoyl ) pyridine
Figure imgf000135_0001
To a mixture of o-chlorophenyl 3-pyridyl ketone (10.0 g, 0.460 mol) and cone. Sulfuric acid at 0°C is added dropwise a mixture of 90% nitric acid (2.40 ml) and cone. Sulfuric acid (6.0 ml). The resultant mixture is stirred one hour at 0°C, poured onto ice and neutralized with 30% ammonium hydroxide. Filtration and drying affords the title compound as a solid (11.4 g, 94.2%) which is identified by mass spectral analysis.
Using essentially the same procedure and the appropriate ketones the following compound are obtained:
Figure imgf000135_0002
mp (°C)
Figure imgf000135_0003
Figure imgf000136_0001
EXAMPLE 19
Preparation of 2-Chlorophenyl- (2-pyrimidinyl) acetonitrile
Figure imgf000136_0002
A mixture of 2-chlorobenzyl cyanide (4.50 g, 0.297 mol), potassium carbonate (6.84 g, 0.0495 mol) and dimethylformamide is stirred 30 minutes at 100°C and treated dropwise with a solution of 2-chloropyrimidine (2.30 g, 0.0201 mol) in dimethylformamide. The resultant mixture is stirred overnight at 100°C and treated with additional 2-chlorobenzyl cyanide (1.54 g, 0.0102 mol). The mixture is stired several more hours at 100°C, cooled and diluted with water. The mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant brown oil is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a brown oil (3.25 g, 70.8%) which is identified by NMR spectral analysis. EXAMPLE 20
Preparation of 2- (2-Chlorobenzoyl)pyrimidine
Figure imgf000137_0001
A mixture of 2-chlorophenyl (2-pyrimidinyl)acetonitile (3.25 g, 0.0142 mol), sodium hydride (60% in mineral oil, 1.07 g, 0.016
]_5 mol) and anhydrous tetrahydrofuran is stirred two hours at reflux and cooled to room temperature. Dry air is bubbled into the mixture while stirring three days. The mixture is quenched by drop- wise addition of a 3:1 water:me hanol mixture and then water. The tetrahydrofuran is removed in vacuo and the aqueous residue
20 filtered to afford the title compound as a brown solid (2.00 g, 64.7%) which is identified by NMR spectral analysis.
EXAMPLE 21
25 Preparation of 2- (4-Fluorobenzoyl) -3-methylpyridine
Figure imgf000137_0002
To a mixture of 4-fluorophenylmagnesium bromide (1.0 M in tetrahydrofuran, 100 ml, 0.100 mol) and tetrahydrofuran at 0°C is added
35 dropwise a solution of 2-cyano-3-methylpyrydine (11.8 g, 0.100 mol) in tetrahydrof ran. The resultant mixture is stirred one hour at 0°C and overnight at room temperature. The mixture is slowly neutralized with 3N hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts are
40 dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a brown liquid (2.32 g, 34.0%) which is identified by NMR spectral analysis.
Using essentially the same procedure on 2-cyanopyridine the fol¬
45 lowing compound is obtained:
Figure imgf000138_0001
EXAMPLE 22
Preparation of 3-Amino-4-fluorophenyl 3-methyl-2-pyridyl ketone
Figure imgf000138_0002
To a mixture of 2- (4-fluoro-5-nitrobenzoyl) -6-methylpyridine (7.13 g, 0.0258 mol) and glacial acetic acid at 70-80°C is added iron powder (7.76 g, 0.130 mol) in three portions. The resultant mixture is stirred overnight at 70-80°C, cooled to room temperature and extracted three times with ethyl acetate. The combined organic layers are filtered through Celite, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a tan solid (4.36 g, 69.8%) which is identified by NMR spectral analysis.
Using essentially the same procedure on 2- (5-nitroben- zoyl) yridine the following compound is obtained:
Figure imgf000138_0003
EXAMPLE 23
Preparation of 4-Amino-5-fluoro-2- (3-methylpicolinoyl) phenyl thiocyanate
Figure imgf000139_0001
To a mixture of 3-amino-4-fluorophenyl 3-methyl-2-pyridyl ketone(4.20 g, 0.171 mol), sodium thiocyanate (4.19 g, 0.0517 mol) and glacial acetic acid is added a solution of bromine in acetic acid (2M, 12 ml, 0.0240 mol) over a one hour period. The resultant mixture is stirred one hour at room temperature and poured into cold water . The precipitate is filtered and dried to afford the title compound as a green solid (5.43 g, >100%) which is identified by NMR and mass spectral analysis.
Using essentially the same procedure on 2- (3-amino-4-fluoroben- zoyl) pyridine the following compound is obtained:
Figure imgf000139_0002
EXAMPLE 24
Preparation of 5-Amino-6-fluoro-3- (3-methyl-2-pyridyl) -1, 2-benz- isothiazole
Figure imgf000140_0001
A mixture of 4-amino-5-fluoro-2- (3-methylpicolinoyl) phenyl thiocyanate (3.06 g, 0.0112 mole), concentrated ammonium hydroxide (300 ml) and methanol (300 ml) is stirred overnight at room temperature. The methanol is removed in vacuo and the resultant mixture is filtered to afford the title compound as a green solid (1/93 g, 66.6%) which is identified by NMR spectral analysis.
Using essentially the same procedure on 2- (3-methyl-2-pyri- doyl) -4-aminophenylthiocyanate the following compound is obtained:
Figure imgf000140_0002
EXAMPLE 25
Preparation of l-Methyl-3- [3- (2-pyridyl) -1,2-benziso- 5 thiazol-5-yl] -6- (trifluoromethyl) uracil N' ' , S, S-trioxide
Figure imgf000141_0001
A mixture of CL 399270 (0.450 g, 11.1 mmol), hydrogen peroxide (30% in water, 5 ml) and glacial acetic acid is stirred one hour 5 at reflux, cooled to room temperature and stirred overnight. The excess peroxide is quenched by addition of saturated sodium sul- fite and the mixture is extracted with hot ethyl acetate. The organic layers are dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow Q semi-solid (0.0800 g, 17.2%) which is identified by NMR and mass spectral analysis.
EXAMPLE 26
5 Preparation of 2, 2' -Dithiobis [5-nitrobenzoic acid]
Figure imgf000141_0002
5 A mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol is treated portionwise with potassium fcerfc-butoxide (55.5 g, 0.495 mol), diluted with additional ethanol, heated to reflux, treated portionwise with a solution prepared from sodium sulfide nonahydrate (60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for two hours, cooled to room temperature, and treated with concentrated hydrochloric acid. The resultant acidic mixture is stirred for one hour and filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a yellow powder which is identified by NMR spectral analysis.
EXAMPLE 27
Preparation of 5-Nitro-l, 2-benzisothiazol-3 (2H) -one
Figure imgf000142_0001
A mixture of 2, 2'-dithiobis [5-nitrobenzoic acid] (44.6 g, 0.113 mol) and thionyl chloride (49.0 mL, 0.670 mol) in methylene chloride is treated with N,N-dimethylformamide (0.800 mL) , refluxed overnight, concentrated in vacuo, and diluted with 1, 2-dichloroe- thane. The resultant organic solution is treated with bromine (22.5 mL, 0.436 mol), stirred at room temperature for 20 minutes, refluxed for 3.5 hours, and concentrated in vacuo to obtain a residue. A solution of the residue in 1,2-dichloroethane is cooled with an ice-water bath, treated with concentrated ammonia (112 mL) over 15 minutes, stirred at room temperature for 16 hours, cooled with an ice-water bath, and treated with concentrated hydrochloric acid. The resultant aqueous mixture is stirred at room temperature for one hour and filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a yellow solid which is identified by NMR spectral analysis.
EXAMPLE 28
Preparation of 3-Chloro-5-nitro-l, 2-benzisothiazole
Figure imgf000142_0002
A mixture of 5-nitro-l, 2-benzisothiazol-3 (2H) -one (10.0 g, 0.0510 mol), phosphorus oxychloride (40.0 mL, 0.429 mol) and tributyl- amine (12.0 mL, 0.050 mol) is heated at 103-115 °C for six hours, stirred at room temperature overnight, and poured into an ice-wa- ter mixture. The resultant aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a gum. Column chromatography of the gum using silica gel and methylene chloride gives the title product as an orange-yellow solid which is identified by NMR spectral analysis.
EXAMPLE 29
Preparation of 3- (3 , 5-Dimethylpyrazol-l-yl) -5-nitro-l, 2-benziso- thiazole
Pyridine
Figure imgf000143_0001
A mixture of 3-chloro-5-nitrobenzisothiazole (5.3g, mmol), 3 , 5-dimethylpyrazole (2.40 g, 25.0 mmol) and pyridine is stirred overnight at reflux, cooled to room temperature and diluted with ethyl acetate. The resultant mixture is filtered and the filtrate is washed with three portions of 10% hydrochloric acid and one portion of water. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound (2.85 g, 43.8%) which is identified by NMR spectral analysis) which is characterized by NMR.
In essentially the same manner, treatment of 3-chloro-5-nitroben- zisothiazole with the appropriate heterocycles affords the folio- wing compounds :
Figure imgf000144_0001
mp (°C)
Figure imgf000144_0002
EXAMPLE 30
Preparation of 5-Amino-3- (3-methylpyrazol-l-yl) -1, 2-benziso- 0 thiazole
Figure imgf000144_0003
0
A mixture of CL 410190 (3.12 g, 12.0 mmol), sodium bicarbonate
(2.00 g, 23.8 mmOl) , acetonitrile and water is stirred one hour at 70°C and treated with sodium hydrosulfite (8.70 g, 50.0 mmol) in portions. The resultant mixture is stirred overnight at re- 5 flux, cooled to room temperature and diluted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is washed with a mixture of methylene chloride and ethyl acetate. The organic layer is decanted to afford the title compound as a viscous brown oil which Q is identified by NMR spectral analysis.
Using essentially the same procedure on the appropriate 5-nitr- obenzisothiazole the following compounds are obtained:
5
Figure imgf000145_0001
p (°C)
Figure imgf000145_0002
EXAMPLE 31
Preparation of 5-Amino-3-chloro-l, 2-benzisothiazole
Figure imgf000145_0003
A solution of 3-chloro-5-nitro-l, 2-benzisothiazole (2.00 g) in toluene is treated with iron powder (8.40 g, 325 mesh) and concentrated hydrochloric acid (8 drops) , heated to reflux, treated dropwise with water (8.00 L) , refluxed for 35 minutes, cooled to room temperature, and filtered through diatomaceous earth. The resultant filtrate is concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1:1) gives the title product. EXAMPLE 32
Preparation of 3- (3-Chloro-l, 2-benzisothiazol-5-yl) -6- (trifluoromethyl) -2,4 (1H,3H) -pyrimidinedione
Figure imgf000146_0001
Figure imgf000146_0002
A mixture of 5-amino-3-chloro-l, 2-benzisothiazole (1.10 g) and 2-dimethylamino-4- (trifluoromethyl) -6H-1, 3-oxazin-6-one (1.38 g) in acetic acid (15.1 mL) is stirred at 90-105 °C for two hours, cooled to room temperature, and filtered to obtain 0.500 g of the title product as a solid. The resultant filtrate is diluted with water and filtered to obtain an additional 1.11 g of the title product.
EXAMPLE 33
Preparation of 3- (3-Chloro-l, 2-benzisothiazol-5-yl) -l-methyl-6- (trifluoromethyl) -2, (IH, 3H) -pyrimidinedione
Figure imgf000146_0003
A mixture of 3- (3-chloro-l,2-benzisothiazol-5-yl) -6- (tri luoromethyl) -2, 4 (IH, 3H) -pyrimidinedione (1.06 g) , potassium carbonate (0.470 g) and iodomethane (0.500 mL) in N,N-dimethyIformamide is stirred at room temperature for 90 minutes, treated with additional iodomethane (0.500 mL) , stirred at room temperature for 15 minutes, and diluted with water. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven at room temperature to give the title product as a solid which is identified by NMR spectral analysis.
EXAMPLE 34
Preparation of 2' -Chloro-4' -fluoro-5' -nitroacetophenone
Figure imgf000147_0001
A 2 M solution of methylzinc chloride in tetrahydrofuran (5, 00 mL, 10.1 mmol) is treated dropwise with a solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (2.00 g, 8.40 mmol) in tetrahydrofuran, treated with tetrakis (triphenylphos - hine) palladium (0) (0.400 g, 0.350 mmol), stirred at room temperature for one hour, and poured into 3 N hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over an- hydrous magnesium sulfate, and concentrated in vacuo to obtain a dark liquid. Flash column chromatography of the liquid using silica gel and a methylene chloride in hexanes solution (6:4) gives the title product as an off-white solid (mp 66-68 °C) which is identified by NMR spectral analyses.
EXAMPLE 35
Preparation of 3-Methyl-5-nitro-l, 2-benzisothiazole
Figure imgf000147_0002
Ammonia (45 g, 2,642 mmol) is bubbled into methanol at -40 °C in a steel bomb. Sulfur (30.5 g, 95.0 mmol) and 2' -chloro-5' -nitroacetophenone (19 g, 95.0 mmol) are then added. The bomb is sealed and heated at about 90 °C overnight. After cooling, the reaction mixture is removed from the bomb and concentrated in vacuo to obtain a residue. The residue is diluted with methylene chloride. passed through a plug of silica gel and concentrated in vacuo to give the title product as an orange solid (12.0 g) which is identified by NMR spectral analyses .
EXAMPLE 36
Preparation of 3- [3- (Bromomethyl) -1, 2-benzisothiazol-5-yl] - l-methyl-6- (trifluoromethyl) -2,4 (1H,3H) -pyrimidinedione and 3- [3- (Dibromomethyl) -l,2-benzisothiazol-5-yl] -l-methyl-6- (tri- fluoromethyl) -2, 4 (IH, 3H) -pyrimidinedione
Figure imgf000148_0001
Figure imgf000148_0002
A mixture of l-methyl-3- (3-methyl-l, 2-benzisothiazol-5-yl) - 6- (trifluoromethyl) -2, 4 (1H,3H) -pyrimidinedione (16.6 g, 48.8 mmol), N-bromosuccinimide (34.8 g, 195 mmol) and benzoyl peroxide (0.295 g, 1.22 mmol) in 1,2-dichloroethane is refluxed for one hour, treated with additional benzoyl peroxide (0.30 g) , refluxed for 3.5 hours, and cooled to room temperature. Column chromatography of the cooled reaction mixture using silica gel and a methylene chloride/hexanes solution (1:1) gives a mixture of the title products which is dissolved in methylene chloride. The resultant organic solution is washed sequentially with 15% sodium hydrogen sulfite solution and water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow solid. Column chromatography of the yellow solid using silica gel and a 1% fcerfc-butyl methyl ether in methylene chloride solution gives 3- [3- (bromomethyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) -2,4 (1H,3H) -pyrimidinedione as an off-white solid, mp 203-204 °C, and 3- [3- (dibromome- thyl) -l,2-benzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) -2,4 (IH, 3H) -pyrimidinedione as an off-white solid, mp 107-110 °C.
Using essentially the same procedure on l-methyl-3- (3-methyl- 6-fluoro-1, 2-benzisothiazol-5-yl) -6- (trifluoromethyl) -2, 4 (1H,3H) pyrimidinedione, the follo^ing compounds are obtained:
Figure imgf000149_0001
i ∑2 mp °C
H Br 185-187
Br Br 239-240
EXAMPLE 37
Preparation of a mixture of 3- [3- (Hydroxymethyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) -2,4 (1H,3H) -pyrimidinedione and 5- [3, 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoro- methyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxaldehyde, (2:3)
CH,
Figure imgf000150_0001
AgBF,
Figure imgf000150_0002
A solution of a 2:3 mixture of 3- [3- (bromomethyl) -1,2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) -2,4 (1H,3H) -pyrimidinedione and 3- [3- (dibromomethyl) -1, 2-benzisothiazol-5-yl] -1-methyl- 6- (trifluoromethyl) -2,4 (1H,3H) -pyrimidinedione (5.00 g) , silver tetrafluoroborate (3.50 g) , 1,4-dioxane (30.0 mL) and water (10.0 mL) is refluxed for 2 hours, cooled, and filtered to remove solids. The resultant filtrate is poured into a methylene chloride and water mixture. The organic phase is separated, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a 2:3 mixture of the title products.
EXAMPLE 38
Preparation of 5- [3 , 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl)-! (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxylic acid
Figure imgf000151_0001
A solution of potassium dichromate (10.0 g) in 1.5 M sulfuric acid (200 mL) is cooled to 0°C, treated dropwise with a solution of a 2:3 mixture of 3- [3- (hydromethyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) -2, 4 (IH, 3H) -pyrimidinedione and 5- [3 , 6-dihydro-3-methyl-2 , 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxaldehyde (12.0 g) in acetic acid, stirred at room temperature for 2 hours, and diluted with water. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a white solid (8.50 g, mp 149-152 °C) . EXAMPLE 39
Preparation of 5- [3, 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxylic acid chloride
Figure imgf000152_0001
To a solution of 5- [3, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxylic acid (0.200 g, 0.000540 mol) in methylene chloride is added N,N-dime- thylformamide (one drop) followed by oxalyl chloride in methylene chloride (2.0 M, 0.540 ml, 0.00108 mol). The resultant mixture is stirred at room temperature for 90 minutes and concentrated in vacuo to a white solid, which is used without further purification.
EXAMPLE 40
Preparation of 5- [3, 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -N- [1- (hydroxymethyl) -2-methyl- propyl] -1, 2-benzisothiazole-3-carboxamide
Figure imgf000153_0001
To a solution of 2-amino3-methyl-l-butanol (1.39 g, 13.5 mmol) in anhydrous tetrahydrofuran at 0°C is added dropwise a solution of 5- [3 , 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) - pyrimidinyl] -1, 2-benzisothiazole-3-carboxylic acid chloride (2.10 g, 5.39 mmol) in tetrahydrofuran. The resultant mixture is stirred 7.5 hours at ambient temperature, diluted with diethyl ether, washed with IM aqueous hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with hexanes-ethyl acetate to afford the title compound as a solid (2.12 g, 86.2%, mp 120°C) which is identified by NMR spec- tral analysis.
Using essentially the same procedure the following product is obtained when CL 149093 is treated with ethanolamine.
Figure imgf000153_0002
mp 130°C
EXAMPLE 41
Preparation of N- [1- (Chloromethyl) -2-methylpropyl] -5- [3, 6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) - pyrimidinyl] -1, 2-benzisothiazole-3-carboxanu.de
Figure imgf000154_0001
To 5- [3 , 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -N- [1- (hydroxymethyl) -2-methylpropyl] -1, 2-benzisothiazole-3-carboxamide (1.89 g, 4.14 mmol) at 0°C is added thionyl chloride (5.00 ml). The resultant mixture is stirred on hour at 0°C and two hours at room temperature. Anhydrous diethyl ether is added and the resultant suspension stirred vigorously for 1.75 hour. The suspension is filtered to afford the title compound as a cream-colored solid (1.77 g, 89.8%, mp >220°C) which is identified by NMR spectral analysis.
Using essentially the same procedure, treatment of CL 411505 with thionyl chloride affords the following product:
Figure imgf000155_0001
mp 196-197°C 0
EXAMPLE 42
Preparation of 3- [3- (4-Isopropyl-2-oxazolin-2-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil 5
Figure imgf000155_0002
To a solution of N- [1- (chloromethyl) -2-methylpropyl] -5- [3 , 6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) - pyrimidinyl] -1, 2-benzisothiazole-3-carboxamide (1.25 g, 2.63 mmol) in anhydrous tetrahydrofuran is added sodium hydride (60% oil dispersion, 0.116 g, 2.90 mmol). The resultant mixture is stirred 1.5 hour at room temperature, quenched with saturated ammonium chloride, diluted with diethyl ether, washed with saturated ammonium chloride and brine, and dried over anhydrous ° magnesium sulfate. Concentration in vacuo affords a yellow syrup, which is combined with material from a previous run and chromatographed on silica gel to afford the title compound as a white crystalline solid (mp 100-105°C) which is identified by NMR spectral analysis. 5
In essentially the same manner, treatment of CL 411506 with so- dium hydride affords the following product:
Figure imgf000156_0001
mp 198-199°C
10
15
20
25
30
35
40
45 EXAMPLE 43
Preparation of l-Acetyl-2- (1, 2-benzisothiazol-3-ylcarbonyl)hydra- zme
H2NNHCQCH Pyridine
Figure imgf000157_0001
Figure imgf000157_0002
To a mixture of acetylhydrazide (6.93 g, 0.0935 mol) and pyridine at 0°C is added a solution of 5- [3 , 6-Dihydro-3-methyl-2, 6- dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benziso- thiazole-3-carboxylic acid chloride (20.3 g, 0.103 mol) in pyridine in four portions such that the temperature does not exceed 40°C. The resultant mixture is heated to reflux, stirred 30 minutes, cooled and concentrated in vacuo. The residue is mixed with ice water and filtered to afford the title compound as an off-white solid (17.5 g, 79.5%) which is identified by NMR analysis.
157
EXAMPLE 44
Preparation of 3- (5-Methyl-l, 3 , 4-thiadiazol-2-yl) -1,2-benziso- thiazole
Figure imgf000158_0001
A mixture of l-acetyl-2- (l,2-benzisothiazol-3-ylcarbonyl) hydra- zine (17.5 g, 0.0744 mol) and phosphorous pentasulfide (53.0 g, 0.119 mol) is heated to 150-160°C. After two hours, the mixture is cooled and the residue carefully digested with warm 2n aqueous sodium hydroxide until gas evolution subsides. The resultant tan solid is filtered and dried to afford the title compound (21.8 g, >100%) which is identified by NMR spectral analysis.
EXAMPLE 45
Preparation of 3- (5-Methyl-l, 3, 4-thiadiazol-2-yl) -5-nitro-l, 2- benzisothiazole
Figure imgf000158_0002
To a mixture of 3- (5-methyl-l, 3, 4-thiadiazol-2-yl) -1,2-benziso- thiazole (6.8 g, 0.0291 mol) and cone, sulfuric acid at 10°C is added 90% nitric acid (3.20 ml, 0.582 mol) dropwise. The resultant mixture is stirred 90 min at 0-10°C and poured into ice water with stirring. Filtration affords a solid which is stirred in hot methylene chloride and filtered to afford the title compound as a tan solid (mp 239-240°C) which is identified by NMR analysis.
EXAMPLE 46
Preparation of l-Benzothiophen-2, 3-dione
Figure imgf000159_0001
To a solution of thiophenol (100 g, 0.907 mol) in ether is added dropwise a solution of oxalyl chloride (175 g, 1.38 mol) in ether. The mixture is stirred two hours at reflux and concentrated in vacuo. The residue is taken up in methylene chloride and cooled to 0 °C. Aluminum chloride (145 g, 1.09 mol) is added in portions such that the temperature does not exceed 25 °C. The resultant mixture is stirred 30 minutes at reflux, cooled to room temperature and poured into ice water with stirring. The organic layer is washed with saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and con- centrated in vacuo to an orange solid which is recrystallized from methylene chloride.-hexanes to afford the title compound (102 g, 69.0%) which is identified by NMR spectral analysis.
EXAMPLE 47
Preparation of 1, 2-Benzisothiazole-3-carboxamide
Figure imgf000159_0002
To ammonium hydroxide (1.78 1) is added l-benzothiophen-2, 3-dione (87.0 g, 0.530 mol) at 5-10 °C, followed by hydrogen peroxide (30% aqueous, 178 ml) . The resultant mixture is filtered to obtain a yellow solid which is dried (77.0 g, 81.7%) and identified as the title compound by NMR and IR spectral analysis. EXAMPLE 48
Preparation of 1, 2-Benzisothiazole-3-carboxylic acid
Figure imgf000160_0001
A mixture of 1, 2-benzisothiazole-3-carboxamide (5.0 g, 0.028 mole) and IN aqueous sodium hydroxide (55 ml) is heated on a steam bath until solution is achieved (approximately 30 minutes) , cooled to room temperature, and acidified with 2N hydrochloric acid. The resulting precipitate is filtered and dried in vacuo to afford the title compound (1.85 g, 96%) as a white solid, which is identified by NMR and IR spectral analysis.
EXAMPLE 49
Preparation of 5-Nitro-l, 2-benzisothiazole-3-carboxylic acid and of 7-Nitro-l,2-benzisothiazole-3-carboxylic acid
Figure imgf000160_0002
+
Figure imgf000160_0003
To a stirred solution of 1, 2-benzisothiazole-3-carboxylic acid (20.0 g, 0.112 mol) in concentrated sulfuric acid (120 ml) at 0°C is added dropwise 90% nitric acid (5.25 ml, 1.3 equivalents) such that the reaction temperature does not exceed 10°C. The solution is stirred for an additional two hours at 10°C, carefully poured into vigorously stirred ice water, and the resulting solid filtered and dried in vacuo to afford a solid (25 g) , which by NMR analysis consists of a 2:1 mixture of 7- and 5-nitro isomers. The above solid is suspended in ethyl acetate, the undissolved solid filtered and recrystallized from ethyl acetate to afford 7-nitro-l,2-benzisothiazole-3-carboxylic acid (3.3 g) identified by NMR spectral analysis.
The initial ethyl acetate filtrate from above is concentrated in vacuo, and the residur recrystallized from acetonitrile (200 ml) to afford 5-nitro-l, 2-benzisothiazole-3-carboxylic acid (6.2 g) as a yellow solid which is identified by NMR spectral analysis. 0
EXAMPLE 50
Preparation of 5-Nitro-l,2-benzisothiazole-3-carboxylic acid chloride 5
Figure imgf000161_0001
To a stirred mixture of 5-nitro-l, 2-benzisothiazole-3-carboxylic acid (5.5 g, 0.0246 mole) and ethylene dichloride (55 ml) is ad- ded thionyl chloride (2.92 g, 1.63 ml, 1.0 eq. ) , and the reaction mixture heated to 70°C. An additional portion of thionyl chloride (1.46 g, 0.82 ml, 0.5 eq) is added and heating at 70°C continued for 2.5 hours. The cooled solution is concentrated in vacuo to afford the title compound which is identified by NMR and IR ana- Q lysis, and used without further purification.
EXAMPLE 51
Preparation of l-Acetyl-2- [ (5-nitro-l, 2-benziso- 5 thiazol-3-yl) carbonyl] hydrazine
Figure imgf000161_0002
To a mixture of acetylhydrazide (90%, 1.84 g, 0.0224 mol) and pyridine at 0-5°C is added dropwise a solution of 5 5-nitro-l, 2-benzisothiazole-3-carboxylic acid chloride (5.96 g, 0.0246 mol) in pyridine. The resultant mixture is brought to reflux, stirred 30 minutes at reflux and cooled to 40°C. The excess pyridine is removed in vacuo and the residue added slowly to ice water with stirring. Filtration affords the title compound as a tan solid (5.22 g, 75.8%) which is characterized by NMR spectral analysis.
EXAMPLE 52
Preparation of 3- (5-Methyl-l, 3, 4-oxadiazol-2-yl) -5-nitro- 1, 2-benzisothiazole
Figure imgf000162_0001
To a mixture of l-acetyl-2- [ (5-nitro-l, 2-benziso- thiazol-3-yl) carbonyl]hydrazine(4.55 g, 0.0163 mol) and acetoni- trile at room temperature is added phosphorous oxychloride (14.9 g, 0.0972 mol). The resultant mixture is heated to reflux, stirred two hours, cooled to room temperature and filtered to afford the title compound as an off-white solid (mp >250°C) which is identified by NMR spectral analysis.
EXAMPLE 53
Preparation of Ethyl α-cyano-5-nitro-l, 2-benzisothiazole-3-ace- tate
Figure imgf000162_0002
A sodium ethoxide solution (previously prepared from ethanol and sodium (1.00 g, 0.0430 mol)) is cooled with an ice-acetone bath, treated portionwise with ethyl cyanoacetate (4.51 g, 0.0398 mol), stirred at room temperature for 30 minutes, treated with 3-chloro-5-nitro-l, 2-benzisothiazole (4.27 g, 0.0199 mol), stirred at room temperature overnight, cooled to 0 °C, and treated dropwise with 10% hydrochloric acid (15.0 mL) . The resultant aqueous mixture is stirred at room temperature for one hour and filtered to obtain a solid. The solid is washed with ethanol and air-dried to give the title product as a yellow solid which is identified by NMR spectral analysis.
EXAMPLE 54
Preparation of Ethyl 5-nitro-l, 2-benzisothiazole-3-acetate
Figure imgf000163_0001
15 Ethyl α-cyano-5-nitro-l,2-benzisothiazole-3-acetate (6,67 g, 0.0229 mol) is added to a solution of acetyl chloride (67.0 mL) in ethanol. The reaction mixture is refluxed overnight, cooled, and filtered to remove solids. The resultant filtrate is concentrated in vacuo to obtain a brown semi-solid. A mixture of the
20 semi-solid in diethyl ether is stirred for two hours and filtered to obtain a solid. The solid is washed with diethyl ether and air-dried to give the title product as yellow crystals (1.04 g, mp 91-92 °C) .
25 EXAMPLE 55
Preparation of Ethyl 5-amino-l, 2-benzisothiazole-3-acetate
Figure imgf000163_0002
35
A 10% acetic acid solution (31.0 mL) is stirred at 50 °C, treated with iron powder (0.656 g) , treated dropwise with a solution of ethyl 5-nitro-l, 2-benzisothiazole-3-acetate (1.03 g, 3.88 mmol) in ethyl acetate, stirred at 50 °C for two hours, treated with ad-
40 ditional iron powder (0.305 g) , stirred at 50 °C for 15 minutes, and poured into saturated sodium hydrogen carbonate solution. The resultant aqueous mixture is extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated
Λ C n vacuo to obtain an oil. Column chromatography of the oil using silica gel and methylene chloride gives the title product as a yellow oil.
EXAMPLE 56
Preparation of Ethyl 5- [3 , 6-dihydro-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-acetate
Figure imgf000164_0001
Figure imgf000164_0002
A mixture of ethyl 5-amino-l, 2-benzisothiazole-3-acetate (0.748 g, 3.16 mmol) and 2-dimethylamino-4- (trifluoromethyl) -6H-1, 3-oxa- zin-6-one (0.660 g, 3.17 mmol) in acetic acid is refluxed for three hours, concentrated in vacuo, and diluted with saturated sodium hydrogen carbonate solution. The resultant mixture is extracted with methylene chloride. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a tan solid which is identified by NMR spectral analysis.
EXAMPLE 57
Preparation of Ethyl 5- [3 , 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1(2H) -pyrimidinyl] -1, 2-benzisothiazole-3-acetate
Figure imgf000165_0001
Figure imgf000165_0002
A mixture of ethyl 5- [3, 6-dihydro-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-acetate (0.643 g, 0.00160 mol) and potassium carbonate (0.243 g, 0.00170 mol) in N,N-dimethylformamide is stirred at room temperature for 90 minutes, treated with iodomethane (0.320 L, 0.00500 mol), stirred at room temperature overnight, and diluted with water. The resultant aqueous mixture is extracted with methylene chloride. The organic extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown oil. Column chromatography of the oil using silica gel and a 10% ethyl acetate in hexanes solution gives the title product as a tan solid (0.362 g, mp 150-152 °C) .
EXAMPLE 58
Preparation of Methyl 5- [3-, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-glyoxylate
Figure imgf000166_0001
A mixture of ethyl 5- [3, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-ace- tate(30.0 g, 0.0750 mol), selenium dioxide (15.0 g, 0.135 mol) and glacial acetic acid is stirred two hours at reflux, cooled and filtered through a pad of Celite. The filtrate is concentra ted in vacuo and the residue is stirred in methylene chloride. The mixture is filtered and the filtrate filtered through a pad of Celite. The resultant filtrate is treated with saturated sodium bicarbonate and solid sodium bicarbonate with stirring until bubbling ceases. The organic layer is saved. The aqueous layer is extracted with methylene chloride. The combined organic layers are washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is stirred overnight in diethyl ether-methylene chloride to afford, after filtration, the title compound as a white solid (24.5 g, 79.0%, mp 101-103°C) which is identified by NMR spectral analysis . EXAMPLE 59
Preparation of Methyl-3- [3- (4-oxo-delta-2-l,2, 5-thiadiazo- lin-3-yl) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil S' , S' -dioxide
Figure imgf000167_0001
A mixture of methyl 5- [3-, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-glyoxy- late(0.750 g, 1.82 mmol), sulfamide (0.869 g, 9.05 mmol) and absolute ethanol is stirred five days at reflux. The resultant mixture is cooled and filtered to afford the title compound as a yellow solid (0.430 g, 51.4%) which is identified by NMR and mass spectral analysis.
EXAMPLE 60
Preparation of 3- [3 [4-Methoxy-2- (ethylimino) -5-oxo-4-imidazo- lidinyl] -l,2-benzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000168_0001
Figure imgf000168_0002
A mixture of methyl 5- [3-, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-glyoxylate (0.0820 g, 1.98 mmol), ethyl guanidine hydrochloride (0.270 g, 2.18 mmol), sodium bicarbonate (0.180 g, 2.14 mmol) and methanol is stirred overnight at reflux, cooled to room temperature and poured into water. The resultant suspension is stirred 20 minutes and filtered with cold water wash to afford the title compound as a white solid (0.610 g, 63.9%, mp 257°C) which is identified by NMR spectral analysis.
Using essentially the same procedure and methyl guanidine hydro- chloride the following product is obtained (mp 205°C) :
Figure imgf000168_0003
Example 61
Preparation of 3- [3- [2- (Dimethylamino) -4-methoxy-5-oxo-2-inidazo- lin-4-yl] -1, 2-benzisothiazol-5-yl] -l-methyl-6- (triflurorme- thyl) uracil
Figure imgf000169_0001
Figure imgf000169_0002
A mixture of methyl 5- [3-, 6-dihydro-3-methyl-2, 6-dioxo-4- (tri - fluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-glyoxylate (0.620 g, 1.50 mmol), dimethyl guanidine hydrochloride (0.200 g, 1.62 mmol), sodium bicarbonate (0.140 g, 1.67 mmol) and methnol is stirred four hours at reflux, cooled to room temperature and partitioned between water and methylene chlotide. The combined organic layers are concentrated in vacuo and the residue is chromatographed on silica gel with methylene chloride-methanol (98:2) to afford the title compound as a solid (0.340 g, 47%, mp
238-240°C) which is identified by NMR spectral analysis.
EXAMPLE 62
Preparation of 3- [3- (4-Hydroxy-5-oxo-2-phenyl-2-imidazolin-4-yl) 1 , 2-benzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000170_0001
Figure imgf000170_0002
A mixture of 5- [3-, 6-dihydro-3-methyl-2 , 6-dioxo-4- (trifluoro- methyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-glyoxylate
(0.620 g, 1.50 mmol), phenyl amidine hydrochloride (0.258 g, 1.65 mmol) and 2-methoxyethanol is stirred 40 minutes at reflux, cooled to room temperature and poured into water. The resultant yellow precipitate is filtered and saved. The filtrate is ex- tracted four times with methylene chloride; the combined organic layers are concentrated in vacuo and the residue is triturated with ether to afford a yellow solid. The yellow solids are combined and chromatographed on silica gel with methylene chloride- methanol to afford the title compound as a solid (0.110 g, 14.6%, mp 139-141°C) which is identified by NMR spectral analysis.
Using essentially the same procedure and tert-butyl amidine hydrochloride, the following product is obtained (mp 192°C) :
Figure imgf000171_0001
EXAMPLE 63
Preparation of 3- [3- (-Hydroxy-5-imino-4,4-dimethyl-2-oxo-3- pyrrolidinyl) -1, 2-benzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000171_0002
Figure imgf000171_0003
A mixture of 5- [3-, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -l,2-benzisothiazole-3-glyoxylate (0.620 g, 1.50 mmol), isopropyl amidine hydrochloride (0.200 g, 1.65 mmol), sodium bicarbonate (0.140 g, 1.67 mmol) and 2-meth- oxyethanol is stirred one hour at reflux, cooled to room temperature and poured into ice water. The resultant suspension is filtered and the filtrate extracted four times with methylene chloride. The combined organic layers are concentrated in vacuo and the residue triturated dwith ether to afford a solid, which is chromatographed on silica gel with methylene chloride-methanol to afford the title compound as a solid (0.270 g, 38.5%, mp 125-127°C)which is identified by NMR spectral analysis. EXAMPLE 64
Preparation of 3- [3- (3 , 4-Dihydro-3-oxo-2-quinoxalinyl) -1, 2-benz- isothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000172_0001
Figure imgf000172_0002
A mixture of 5- [3-, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoro- methyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-glyoxylate (0.7500 g, 1.81 mmol), 1, 2-diaminobenzene (0.200 g, 1.84 mmol) and ethanol is stirred 16" hours at reflux and filtered hot. The filtrate is concentrated in vacuo to afford the title compound as a light yellow solid (0.480 g, 56.3%, mp >250°C) which is identi- fied by NMR analysis.
In essentially the same manner, treatment of CL 411406 with dia- minomaleonitrile affords The following compound as a white solid
(mp >250°C) :
Figure imgf000173_0001
EXAMPLE 65
Preparation of 3- [3- (4, 6-Diethoxy-2-pyrimidinyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000173_0002
To a cooled mixture of 5- [3, 6-Dihydro-3-methyl-2, 6-dioxo-4- (tri - fluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxylic acid (3.71 g, 10.0 mmol), diethyl ether and N,N-dimethylformamide (3.0 ml) is added oxalyl chloride (1.52 g, 12.0 mmol) . The mixture is allowed to warm to room temperature and stirred overnight. The mixture is allowed to settle and the supernatant is decanted and concentrated in vacuo. The residue is taken up in methylene chloride and added dropwise to a stirred mixture of diethyl malonimidate dihydrochloride (2.31 g, 10.0 mmol), diiso- propylethylamine (10 ml) and methylene chloride at -40°C over one hour. The resultant mixture is allowed to warm to room temperature, diluted with methylene chloride, washed with water, 10% aqueous hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (0.410 g, 8.31%, mp 197-200°C) hich is identified by NMR spectral analysis. EXAMPLE 66
Preparation of 5- [3 , 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxaldehyde
Figure imgf000174_0001
Figure imgf000174_0002
A solution of 3- [3- (dibromomethyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) -2,4 (1H,3H) -pyrimidinedione (0.500 g, 0.00100 mol) in a dioxane/water mixture (5:2) is treated with silver nitrate (0.340 g, 0.00200 mol), refluxed for 90 minutes, cooled to and stirred at room temperature overnight, refluxed for three hours, cooled, and filtered through a pad of diatomaceous earth. The resultant filtrate is concentrated in vacuo to obtain an aqueous mixture. The aqueous mixture is extracted with methylene chloride. The organic extract is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Column chromatography of the solid using silica gel and methylene chloride gives the title product as a solid (0.240 g, mp 193-194.5°C) .
Using essentially the same procedure on 3- [6-fluoro-3- (dibromomethyl) -1, 2-benzisothiazol-5-yl] -l-methyl-6- (trifluoro- methyl) -2,4 (1H,3H) -pyrimidinedione, 5-[3,6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimid- nyl-6-fluoro-1, 2-benzisothiazole-3-carboxaldehyde is obtained. EXAMPLE 67
Preparation of l-Methyl-6- (trifluoromethyl) -3- (3-vale- ryl-1, 2-benzisothiazol-5-yl) -2 , 4 (IH, 3H) -pyrimidinedione
Figure imgf000175_0001
Figure imgf000175_0002
To a solution of 5- [3, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxylic acid (0.200 g, 0.000540 mol) in methylene chloride is added N,N-dime- thylformamide (one drop) followed by oxalyl chloride in methylene chloride (2.0 M, 0.540 ml, 0.00108 mol). The resultant mixture is stirred at room temperature for 90 minutes and concentrated in vacuo to a white solid, which is saved. To a suspension of copper cyanide (0.061 g, 0.000675 mol) in tetrahydrofuran, is added dropwise n-butyllithium (2.5 M in hexanes, 0.540 ml, 0.00135 mol) at -78°C. The reaction mixture is allowed to warm for 5 minutes and then cooled back to -78°C. The mixture is then treated with a solution of the white solid from the first step in tetrahydrofuran, and the resultant mixture stirred one hour at -78°C. The reaction mixture is quenched with saturated ammonium chloride and diluted with ethyl acetate. The organic layer is washed sequentially with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a yellow syrup. Chromatography of the syrup on silica gel using hexanes : ethyl acetate gives the title compound as a colorless syrup (0.142 g, 64.0%) which is identified by NMR spectral analysis.
Using essentially the same procedure, the following compounds are obtained:
Figure imgf000176_0001
Sl2 HID °C
C (CH3 ) 3 83 -85
C6H5 93-95
CH (CH3 ) CH2CH3 75-77
EXAMPLE 68
Preparation of 3- [3- (4, 6-Dimethyl-2-pyrimidinyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000176_0002
Figure imgf000176_0003
A stirred mixture of 5- [3 , 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxal- dehyde (3.35 g, 10.0 mmol), 2, 4-pentanedione (1.00 g, 10.4 mmol), ammonium acetate (8.00 g, 10.4 mmol), glacial acetic acid and dimethylsulfoxide is heated to 80-90°C and stirred overnight while air is bubbled through the mixture at 80-90°C. The mixture is cooled to room temperature and diluted with chloroform. The organic layer is washed five times with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel to afford the title compound as a yellow solid (1.68 g, 40.1%) which is identified by NMR spectral analysis.
EXAMPLE 69
Preparation of 3- [3- (1, 3-Dioxolan-2-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000177_0001
A mixture of 3- [3- (Dibromomethyl) -1, 2-benzisothiazol-5-yl] - l-methyl-6- (trifluoromethyl) -2 , 4 (IH, 3H) -pyrimidinedione (0.500 g, 10.0 mmol), silver trifluoromethanesulfonate (0.500 g, 19.5 mmol), ethylene glycol (5.00 ml) , dichloromethane and dimethoxy- methane is stirred three days at room temperature and treated with additional silver trifluoromethanesulfonate (0.300 g, 11.7 mmol) . The resultant mixture is stirred one day at room temperature and treated with additional silver trifluoromethane- sulfonate (0.400 g, 15.6 mmol) and ethylene glycol (1.00 ml), stirred another day at room temperature and treated again with silver trifluoromethanesulfonate (0.300 g, 11.7 mmol) and ethylene glycol (1.0 ml) . After stirring an additional day the mixture is filtered. The filtrate is diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is triturated with hexanes-ethyl ace- tate to afford the title compound as a white solid (0.070 g,
17.5%, mp 213-216°C) which is identified by NMR spectral analysis. EXAMPLE 70
Preparation of l-Methyl-3- [3- (4-methyl-l, 3-dioxolan-2-yl) ■ l,2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
Figure imgf000178_0001
A mixture of 5- [3 , 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoro- methyl) -1 (2H) -pyrimidinyl] -l,2-benzisothiazole-3-carboxaldehyde (0.500 g, 1.41 mmol), 1, 2-propanediol (0.130 ml, 1.83 mmol), p-toluenesulfonic acid (0.0100 g, 0.0100 g, 0.071 mmol) and toluene is stirred at reflux with azeotropic removal of water overnight, cooled to room temperature, diluted with diethyl ether, washed twice with water and once with brine and dried over anhydrous magnesium sulfate. Concentration in vacuo affords a yellow oil, which is chromatographed on silica gel to afford the title compound as a yellow solid (0.510 g, 87.6%, mp 81-83°C)which is identified by NMR spectral analysis.
Using essentially the same procedure, treatment of various aldehydes or ketones with the appropriate diols affords the following compounds :
Figure imgf000178_0002
ω ω t t I-1 I-1 in o o in o o in
l-H HH HM K K K ffi K W K ^I K 'il 'il ffi K K K W
Figure imgf000179_0001
l-> H1 I-1 3
00 1-0 O o o σ. o •a CTi -J -J
00 t 1 1 1 1 1 00 00 00 o m ω ω co M H t σi cD oo
!£> lO H1 H1 H1 o I I I I I I I I I I I
ISJ 00 H1 o (-1 Ω -J oo oo D 00 I-1 00 H1 3 1-0 "o σ -> C l -J
UI O - — w ω ω CO o ι _ ι U M to o
179
H CH3 H H CH3 CH3 100-102
F H H H H H 105-109
F CH3 H H CH3 (cis) H 80-83
l-Methyl-3- [3- (5-methylene-m-dioxan-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) -2, 4 (1H,3H) -pyrimidone:
Figure imgf000180_0001
mp 87-90°C
Using essentially the same procedure with 5-[3,6-Di- hydro-3-methyl-2, 6-dioxo-4- (trifluoro- methyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxaldehyde and 2-mercaptoethanol the following product is obtained
Figure imgf000180_0002
mp 230-232°C
EXAMPLE 71
Preparation of l-Methyl-3- [3- [4- [ (methylsulfonyl) methyl] - 1, 3-dioxolan-2-yl] -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil (two diasereoisomers)
Figure imgf000181_0001
(2 diastereomers)
20 A mixture of l-methyl-3- [3- [4- [ (methylthio)methyl] -1, 3- dioxolan-2-yl] -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil (1.20 g, 26.1 mmol), m-chloroperbenzoic acid (75%, 0.620 g, 26.1 mmole) and methylene chloride is stirred two hours at room temperature, treated with additional ) , m-chloroperbenzoic acid
25 (0.620 g, 26.1 mmole) and stirred one hour at room temperature. The mixture is concentrated in vacuo. The residue is taken up in ethyl acetate and washed twice with 5% aqueous sodium carbonate and once with water. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to a pale yellow oil, _0 which is chromatographed on silica gel with ethyl acetate-hexanes, resulting in separation of the two diastereomers. The first diastereomer is isolated as a white solid (0.040 g, 32.0%, mp 184-186°C) and the second is isolated as a white solid (0.380 g, 29.7%, mp 112-117°C) .
35
40
45 EXAMPLE 72
Preparation of l-Methyl-3- [3- [4- [ (methylsulfinyl)methyl] - 1, 3-dioxolan-2-yl] -l,2-benzisothiazol-5-yl] -6- (trifluoro- methyl) uracil
Figure imgf000182_0001
A mixture of l-methyl-3- [3- [4- [ (methyl - thio) methyl] -1, 3-dioxolan-2-yl] -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil (0.970 g, 21.1 mmol), m-chloroperbenzoic acid (70%, 0.500 g, 21.1 mmol) and methylene chloride is stirred one hour at room temperature and concentrated in vacuo. The residue is taken up in ethyl acetate and washed twice with 5% aqueous so- dium carbonate and once with brine. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to a white solid, which is chromatographed on silica gel with ethanol- ethyl acetate to afford the title compound as a white solid (0.700 g, 70.0%, mp 72-75°C) which is identified by IR and NMR spectral analysis. EXAMPLE 73
Preparation of [2- [5- [3 , 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benziso- thiazol-3-1] -1, 3-dioxolan-4-yl] methyl thiocyanate
NaSCN
Figure imgf000183_0001
A mixture of 3- [3- [4- (bromomethyl) -1, 3-dioxolan-2-yl] -1-methyl- 6- (trifluoromethyl) uracil (0.500 g, 1.02 mmol), sodium thiocyanate (0.410 g, 5.06 mmol) and dimethyl sulfoxide is stirred at 70°C for 24 hours, treated with additional sodium thiocyanate (0.290 g, 3.58 mmol) and stirred overnight at 70°C. The resultant mixture is treated again with sodium thiocyanate (0.220 g, 2.71 mmol) , stirred several hours at 70°C, treated with more sodium thiocyanate (0.16 g, 1.97 mmol), stirred several more hours at 70°C and cooled to room temperature. The mixture is poured into water and extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a yellow oil, which is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a white solid (0.340 g, 70.8%, mp 75°C) which is identified by IR and NMR analysis.
EXAMPLE 74
Preparation of 3- [3- [5- (Bromomethyl) -5-hydroxy-m-dia- xan-2-yl] -1, 2-benzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000184_0001
To a mixture of l-methyl-3- [3- (5-methylene-m-dioxan-2-yl) - l,2-benzisothiazol-5-yl] -6- (trifluoromethyl) -2,4 (1H,3H) -pyrimi- done (1.00 g, 2.35 mmol), water and dioxane is added N-bromosuccinimide (0.500 g, 2.81 g, mmol). The resultant mixture is stirred overnight at room temperature, poured into water and extracted twice with diethyl ether. The organic layers are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with diethyl ether-methylene chloride to afford the title compound as a white solid (1.00 g, 81.3%, mp 105-110°C) which is identified by IR and NMR spectral analysis.
EXAMPLE 75
Preparation of l-Methyl-3- (3-spiro [m-diox- ane-5,2'-oxiran] -2-yl-l, 2-benzisothiazol-5-yl) -6- (trifluoro- methyl) uracil
Figure imgf000185_0001
To a mixture of 3- [3- [5- (bromomethyl) -5-hydroxy-m-dio- xan-2-yl] -1, 2-benzisothiazol-5-yl] -l-methyl-6- (trifluoro- methyl) uracil (0.580 g, 1.11 mmol) and tetrahydrofuran at 5°C is added sodium hydride (60% dispersion in mineral oil, 0.0400 g, 1.11 mmol). The resultant mixture is stirred overnight at ambient temperature and treated with additional sodium hydride ( 0.0400 g, 1.11 mmol). The mixture is poured into saturated ammonium chloride and extracted twice with diethyl ether. The combined organic extracts are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with diethyl ether-methylene chloride to afford the title compound (0.0800 g, 16.3%, mp 203-206°C) which is identified by NMR spectral analysis. EXAMPLE 76
Preparation of 3- [3- (1, 3-Dithiolan-2-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000186_0001
To a mixture of 5- [3 , 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxaldehyde (0.300 g, 0.850 mmol) and methylene chloride is added ethanedi- thiol (0.0940 g, 1.00 mmol) and boron trifluoride-etherate (0.200 ml) . The resultant mixture is stirred overnight at room temperature and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to a yellow solid which is stirred in hot methylcyclohexane and filtered to afford the title compound as a light yellow solid (0.170 g, 46.3%, mp 227-232°C) which is identified by NMR spectral analysis.
EXAMPLE 77
Preparation of 3- [3- (3, 6-Dihydro-4, 6, 6-trimethyl-2H-py- ran-2-yl) -1, 2-benzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000187_0001
A mixture of 5- [3 , 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxalde- hyde(0.500 g, 0.00141 mol), 2 , 4-dimethyl-2 , 4-pentanediol (0.260 g, 0.00183 mol), p-toluenesulfonic acid (0.0100 g, 0.000071 mol) and toluene is stirred overnight at reflux with azeotropic remo- val of water. The mixture is cooled to room temperature, diluted with diethyl ether and ethyl acetate and washed with two pror- tions of water and brine. The organic layer is dried and concentrated in vacuo to a brown oil, which is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a white solid (0.200 g, 31.4%, mp 88-92°C) which is characterized by NMR spectral analysis. EXAMPLE 78
Preparation of Ethyl (R) -2- [5- [3 , 6-dihydro-3-methyl-2 , 6- dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1,2-benziso- thiazol-3-yl] -4-thiazolidinecarboxylate
Figure imgf000188_0001
25 To a mixture of L-cysteine ethyl ester hydrochloride (0.580 g, 3.12 mmol), potassium acetate (0.300 g, 3.06 mmol) and 50% acetone-water is added dropwise a solution 5-[3,6-Di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] - 1, 2-benzisothiazole-3-carboxaldehyde (1.00 g, 2.81 mmol) in ace¬
30 tone. The resultant mixture is stirred four days at room temperature and treated with additional L-cysteine ethyl ester hydrochloride (0.580 g, 3.12 mmol) and, potassium acetate (0.300 g, 3.06 mmol). The resultant mixture is warmed to 35°C and stirred overnight. The mixture is concentrated in vacuo and the re¬
35 sidue is extracted with methylene chloride. The organic layer is washed with water, treated with charcoal, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with methylene chloride-ethyl acetate to afford the title compound as an off-white solid (0.600 g,
40 43.9%, mp 97-98 °C) which is identified by NMR spectral analysis.
45 EXAMPLE 79
Preparation of 3- [3- (3-Butyl-2-thiazolidinyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000189_0001
A mixture of 5- [3 , 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxaldehyde (0.500 g, 1.41 mmol), 2- (butylamino) ethanethiol (0.250 ml, 1.69 mmol) , ethanol and tetrahydrofuran is stirred overnight at room temperature and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a light yellow solid (0.170 g, 25.6%, mp 78-82°C) which is identified by NMR spectral analysis.
EXAMPLE 80
Preparation of 3-Acetyl-2- [5- [3, 6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoro- methyl) -1(2H) -pyrimidinyl] -1, 2-benzisothiazol-3-yl] thiazolidine
Figure imgf000190_0001
A mixture of 5- [3, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxaldehyde (0.500 g, 1.41 mmol), 2-aminoethanethiol (0.13 g, 1.69 mmol), ethanol and tetrahydrofuran is stirred overnight at room temperature. The mixture is concentrated in vacuo and the residue taken up in methylene chloride. The resultant mixture is treated with triethylamine (0.340 ml, 2.41 mmol), then acetyl chloride (0.120 ml, 1.69 mmol), stirred 90 minutes and poured into water. The resultant mixture is diluted with methylene chloide. The organic layer is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a white solid, which is chromatographed on silica gel with methanol-me- thylene chloride to afford the title compound as a white solid (0.600 g, 93.3%, mp 135-140°C) which is identified by NMR spectral analysis .
Using essentially the same procedure with CL 397449, 2-aminoethanethiol and benzoyl chloride the following compound is obtained: 190
Figure imgf000191_0001
mp 148-152°C
EXAMPLE 81
Preparation of l-Methyl-3- [3- (1, 3-oxathian-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
Figure imgf000191_0002
A mixture of 5- [3 , 6-dihydro-3-methyl-2 , 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxaldehyde (2.68 g, 8.05 mmol), 3-mercapto-l-propanol (0.600 ml, 6.84 mmol), bismuth (III) chloride (0.090 g, 0.290 mol) and acetonitrile is stirred overnight at room temperature. Additional ) , 3-mercapto-l-propanol (0.200 ml, 2.28 mmol) and ), bismuth (III) chloride are added and the resultant mixture is concentrated in vacuo. The residue is chromatographed with ethyl acetate-hexanes to afford a solid, which is taken up in diethyl ether, washed with water, once with brine and dried over anhydrous magnesium sulfate. Concentration in vacuo affords the title compound as a white solid (1.15 g, 33.2%, mp 125-130°C) which is identified by NMR spectral analysis. EXAMPLE 82
Preparation of l-Methyl-3- [3- (l,3-oxathian-2-yl) -1,2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil S' , S' -dioxide
Figure imgf000192_0001
A mixture of l-methyl-3- [3- (1, 3-σxathi n-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil (0.960 g, 2.24 mmol), m-chloroperbenzoic acid (72%, 0.790 g, 3.30 mmol) and methylene chloride is stirred one hour at room temperature, poured into saturated sodium bicarbonate and extracted twice with ethyl acetate. The combined organic layers are washed with 5% aqueous sodium carbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant white solid is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a white solid (0.75 g, 72.6%, mp >230°C) which is identified by NMR spectral analysis.
Using essentially the same procedure on CL 410143 affords the following product:
Figure imgf000192_0002
mp 219-222°C EXAMPLE 83
Preparation of l-Methyl-3- (3-propenyl-l,2-benziso- thiazol-5-yl) -6- (trifluoromethyl) -2,4 (IH, 3H) -pyrimidinedione, (Z)- and l-Methyl-3-propenyl-l,2-benzisothiazol-5-yl) -6- (trifluoromethyl) -2,4 (1H,3H) -pyrimidinedione, (E)- and (Z)-, (3:11
2CH3Br"
Figure imgf000193_0001
CH3
Figure imgf000193_0002
A mixture of (ethyl) triphenylphosphoniu bromide (1.15 g, 0.00310 mol) in tetrahydrofuran is treated with sodium hydride (0.120 g, 0.00310 mol), stirred at room temperature for one hour, treated with a mixture of 5- [3 , 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoro- methyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-carboxaldehyde (1.00 g, 0.00280 mol) in tetrahydrofuran, stirred at room temperature for one hour, and filtered. The resultant filtrate is partially concentrated in vacuo, diluted with methylene chloride, washed sequentially with water and brine, dried over anhy- drous magnesium sulfate, and concentrated in vacuo to obtain an orange solid. Flash column chromatography of the solid using silica gel and a 1% diethyl ether in methylene chloride solution gives l-methyl-3- (3-propenyl-l,2-benzisothiazol-5-yl) -6- (trifluoromethyl) -2, 4 (IH, 3H) -pyrimidinedione, (Z)- as a white solid (0.350 g, mp 200-201 °C) and l-methyl-3- (3-propenyl-l, 2-benziso- thiazol-5-yl) -6- (trifluoromethyl) -2 , 4 (IH, 3H) -pyrimidinedione, (E)- and (Z)-, (3:1) as a white solid (0.450 g, mp 228-230 °C) .
Following essentially the same procedure and using the appropria- tely substituted phosphoniu bromide, the following compounds are obtained:
Figure imgf000194_0001
io En mp °C
C02CH3 H >230
C(0)CH3 H >230
CHO H >230
CH2Br H 235 (dec)
C(0)C6H5 H
C(0)N(CH3)OCH3 H
C02CH2=CH2 H
CHO CH2CH3
EXAMPLE 84
Preparation of 3- [3- (2 (and 1) -Bromo-1 (and 2)-hydroxy- propyl) -l,2-benzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) -2 , 4 (IH, 3H) -pyrimidinedione, (4:1) mixture of diastereomers
Figure imgf000195_0001
To a mixture of 1-methyl- (3-propenyl-l,2-benziso- thiazol-5-yl) -6- (trifluoromethyl) -2 , 4 (IH, 3H) -pyrimidinedione (1.00 g, 0.00272 mol), dioxane and water is added N-bromosuccinimide (0.570 g, 0.00321 mol). The resultant mixture is stirred 23 hours at room temperature, poured into water and extracted with ether. The organic layers are washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a yellow foam. The foam is chromatographed on silica gel with methylene chloride: ether to afford the title mixture of isomers as a white foam (1.03 g, 82.4%, mp 100-103 °C) which is identified by NMR spectral analysis. EXAMPLE 85
Preparation of 3- [3- [ (1R,2S) -1,2-Epoxypropyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil and 3- [3- [ (1R,2R) -1,2-Epoxypropyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000196_0001
Figure imgf000196_0002
To a solution of CL 399500 (0.760g, 1.60 mmol) in tetrahydrofuran at 5°C is added sodium hydride (60% in mineral oil, 0.0640g, 1.60 mmol) . The resultant mixture is stirred 30 min at ambient temperature, diluted with diethyl ether, washed with water and brine and dried over magnesium sulfate. Concentration in vacuo affords a white foam, which is chromatographed on silica gel with methylene chloride-diethyl ether. CL 399537 elutes first as a white foam (0.210 g, 34.5%, mp 172-176°C) followed by CL 399538 as a white solid (0.16 g, 26.2%, mp 156-160°C) . Both products were identified by IR and NMR spectral analysis. EMAMPLE 86
Preparation of 5- [3, 6-Dihydro-3-methyl-2, 6-dioxo-4- (trifluoro- methyl) -1 (2H) -pyrimidinyl] -1, 2-benzisothiazole-3-malononitrile
Figure imgf000197_0001
Figure imgf000197_0002
A mixture of 3- (3-chloro-l,2-benzisothiazol-5-yl) -l-methyl-6-
(trifluoromethyl) -2,4 (IH, 3H) -pyrimidinedione (0.500 g) , malononi- trile (0.270 g) and triethylamine (1.50 g) in methyl sulfoxide is stirred at 60 °C for 15 minutes, cooled to room temperature, and diluted with water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown oil. The extracted aqueous phase is diluted with brine, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a brown oil. Flash column chromatography of the combined oils using silica gel and an ethyl acetate/hexanes/methanol/acetic acid solution (10:10:4:1) gives the title product as an oil which is identified by NMR spectral analyses. EXAMPLE 87
Postemergence herbicidal evaluation of test compounds
The postemergence herbicidal activity of the compounds of the present invention is demonstrated by the following tests wherein a variety of dicotyledonous and monocotyledonous plants are treated with test compounds. In the tests, seedling plants are grown in jiffy flats for about two weeks. The test compounds are dispersed in 50/50 acetone/water mixtures containing 0.5% TWEEN®20, a polyoxyethylene sorbitan monolaurate surfactant of Atlas Chemical Industries, in sufficient quantities to provide the equivalent of about 0.0157 kg to 0.500 kg per hectare of active compound when applied to the plants through a spray nozzle operating at 40 psi for a predetermined time. After spraying, the plants are placed on greenhouse benches and are cared for in accordance with conventional greenhouse procedures. From four to five weeks after treatment, the seedling plants are examined and rated according to the rating system set forth below. Data obtained are reported in Table I below. Where more than one test is involved for a given compound, the data are averaged.
Plant species employed in these evaluations are reported by hea- der abbreviation, common name and scientific name.
Compounds employed in this postemergence herbicidal evaluation are given a compound number and identified by name. Data in Table I are reported by compound number.
Herbicide Rating Scale
Results of herbicide evaluation are expressed on a rating scale (0-9) . The scale is based upon a visual observation of plant stand, vigor, malformation, size, chlorosis and overall plant appearance as compared with a control.
% Control Rating Meaning Compared to Check
9 Complete kill 100
8 Approaching Complete Kill 91-99
7 Good Herbicidal Effect 80-90
6 Herbicidal Effect 65-79
5 Definite Injury 45-64
4 Injury 30-44
3 Moderate Effect 16-29 % Control
Ratinσ Meaning Compared to Check
2 Slight Effect 6-15
1 Trace Effect 1-5
0 No Effect 0
A "blank space" indicates that no evaluation was conducted.
PLANT SPECIES EMPLOYED IN HERBICIDAL EVALUATIONS
Header Abbr. Common Name Scientific Name
ABUTH Velvetleaf Abut i Ion theophrasti , Medic.
AMBEL Ragweed, Common Ambrosia artemisifσlia, L .
CASOB Sicklepod Cassia obtusifolia, L.
CHEAL Lambsquarters , Common Chenopodium album, L.
GALAP Galium Galium aparine
IPOHE Morningglory, Ivyleaf Ipomoea hederacea, (L.)
Jacq.
IPOSS Morningglory Spp, Ipomoea Spp.
ECHCG Barnyardgrass Echinochloa crus-galli , (L . ) Beau
SETVI Foxtail , Green Set aria viridis, (L . ) Beau Header Abbr. Common Name Scientific Name
GLXMAW Soybean, Williams Glycine max, (L.) Merr. cv Williams
GLXMA Soybean Glycine max, (L.) Merr.
ORYSAT Rice, Tebonnet Ory∑a sa tiva, (L.) Tebonnet
TRZAWR Wheat, Winter, Tri ti cum aestivum, cv Riband cv Riband
ZEAMX Corn, Field Zea mays, L.
COMPOUNDS EVALUATED AS HERBICIDAL AGENTS
Compound Number
1 397688 l-methyl-3- [3- (3-thienyl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
2 397753 ethyl (R) -2- [5- [3, 6-dihydro-3-methyl-
2, 6-dioxo-4- (trifluoromethyl) -1 (2H) - pyrimidinyl] -1, 2-benzisothiazol-3-yl] - 4-thiazolidinecarboxylate
3 397828 l-methyl-3- [3- (2-thienyl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
4 397830 l-methyl-3- [3- (3-methyl-2-thienyl) -1, 2-b enzisothiazol-5-yl] -6- (trifluoromethyl) uracil
5 397903 l-methyl-3- [3- (l-methylimidazol-2-yl) -
1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
6 399079 l-methyl-3- [3- (l-methylpyrrol-2-yl) -1,2- benzisothiazol-5-yl] -6- (trifluoromethyl) uracil Compound
Number
7 399086 l-methyl-3- [3- (4-methyl-2-thiazolyl) -1,2 -benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
399179 3- [3- (2 , 5-diethyl-3-thienyl) -1, 2-benz - isothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
399270 l-methyl-3- [3- (2-pyrodyl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
10 399343 3- [3- (3-methoxy-2-thienyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoro- methyl) uracil
11 399425 l-methyl-3- [3- (3-pyridyl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil 12 399517 l-methyl-3- [3- (2-pyrimidinyl) -1, 2-benz - isothiazol-5-yl] -6- (trifluoromethyl) uracil
13 399537 3- [3- [ (IR, 2S) -1, 2-epoxypropyl] -1, 2-benz - isothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
14 399538 3- [3- [ (IR, 2R) -1, 2-epoxypropyl] -1, 2-benz - isothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil 15 399566 l-methyl-3- [3- (2-pyridyl) -1, 2-benziso - thiazol-5-yl] -6- (trifluoromethyl) uracil N' ' , S, S-trioxide
16 399653 l-methyl-3- [3- (5-methyl-l, 3 , 4-oxadiazol- 2-yl) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
17 399741 l-methyl-3- [3- (5-methyl-l, 3 , 4-thiadiazol
-2-yl) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
18 399753 1 , 2-benzisothiazole-3-carboxanilide,
4 ' -chloro-5- [3 , 6-dihydro-3-methyl- 2 , 6-dioxo-4- ( trif luoromethyl) -1 (2H) - pyrimidinyl] -N-methyl- Compound
Number
19 399766 l-methyl-3- [3- (3-methyl-2-pyridyl) -1,2-b enzisothiazol-5-yl] -6- (trifluoromethyl) uracil
20 399854 N- [3- (5-methyl-2-thienyl) -1, 2-benziso- thiazol-5-yl] -l-cyclohexene-l,2-dicar- boximide
21 399855 l-methyl-3- [3- (5-methyl-2-thienyl) -1,2-b enzisothiazol-5-yl] -6- (trifluoromethyl) uracil
22 399857 Methyl [ (2- [5- [3, 6-dihydro-3-methyl-2, 6- dioxo-4- (trifluoromethyl) -1 (2H) - pyrimidinyl] -1, 2-benzisothiazol-3-yl] -3- thienyl] oxy] acetate
23 399858 methyl 2- [ (2- [5- [3, 6-dihydro-3-methyl- 2 , 6-dioxo-4- (trifluoromethyl) -1 (2H) - pyrimidinyl] -1, 2-benzisothiazol-3-yl] - 3-thienyl] oxy] ropionate
24 410061 3- [3- (1, 3-dithiolan-2-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
25 410062 3- [6-fluoro-3- (2-pyridyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
26 410095 l-methyl-3- [3- (4-methyl-3-thienyl) -1,2-b enzisothiazol-5-yl] -6- (trifluoromethyl) uracil 27 410111 3- [3- (3 , 5-dimethyl-2~thienyl) -1, 2-benz - isothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
28 410115 3-(3-m-dioxan-2-yl-l,2-benziso- thiazol-5-yl) -l-methyl-6- (trifluoromethyl) uracil
29 410116 3-acetyl-2-[5-[3,6-dihydro-3-methyl- 2, 6-dioxo-4- (trifluoromethyl) -1 (2H) - pyrimidinyl] -1, 2-benzisothiazol-3-yl] thiazolidine Compound
Number
30 410122 3-benzoyl-2- [5- [3 , 6-dihydro-3-methy1- 2 , 6-dioxo-4- (trifluoromethyl) -1 (2H) - pyrimidinyl] -1, 2-benzisothiazol-3- yl] thiazolidine
31 410143 l-methyl-3- [3- (1, 3-oxathiolan-2-yl) -
1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
32 410223 l-methyl-3- [3- (l,3-oxathioln-2-yl) -1, 2- benzisothiazol-5-yl] -6- (trifluoromethyl) uracil S' , S' -dioxide
33 410225 l,2-benzisothiazole-3-carboxaldehyde, 5- [3 , 6-dihydro-3-methyl-2 , 6-dioxo- 4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -, 3- [bis (2-hydroxyethyl) dithioacetal]
34 410275 l-methyl-3- [3- (1, 3-oxathian-2-yl) -1,2 -benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
35 410290 l-methyl-3- [3- (1, 3-oxathian-2-yl) -1,2- benzisothiazol-5-yl] -6- (trifluoromethyl) uracil S' , S'-dioxide
36 410291 3- [3 (5, 5-dimethyl-m-dioxan-2-yl) -
1, 2-benzisothiazol-5-yl] -1- methyl-6- (trifluoromethyl) racil
37 410309 l-methyl-3- [3- (4-methyl-m-dioxan-2-yl)
1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil 38 410312 l-methyl-3- [3- (3-methylpyrazol-l-yl) -
1, 2-benzisothiazol-5-yl] -6- ( trifluoro- methi) uracil
39 410384 2-propynyl [ [2- [5- [3, 6-dihydro-3-methy1-
2 , 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benziso - thiazol-3-yl] -3-thienyl] oxy] acetate
40 410399 3- [3- (4 , 6-dimethyl-2-pyrimidinyl) -1, 2-be nzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil Compound Number
41 410228 3- [3- (3-methoxy-2-pyridyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
42 410504 l-methyl-3- [3- (5-methyl-2-pyridyl) -1,2-b enzisothiazol-5-yl] -6- (trifluoromethyl) uracil
43 410597 3- [3- (4, 6-diethoxy-2-pyrimidinyl) -1, 2-be nzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
44 410815 3-[6-fluoro-3-(3-methyl-2-pyridyl)-l,2-b enzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
45 410850 3-[3-(l,3-dioxolan-2-yl)-l,2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
46 410875 N- [6-fluoro-3- (3-methyl-2-pyridyl) -1, 2-b enzisothiazol-5-yl] -1-cyclohex- ene-l,2-dicarboximide
47 411010 3- [3- [(4R,5S) -4, 5-dimethyl-l, 3-dioxolan-
2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
48 411011 3- [3- [ (4R,5R) -4, 5-dimethyl-l, 3-dioxolan-
2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil 49 411019 l-methyl-6- (trifluoromethyl) -3- [3- (3,4, 5-trimethyl' pyrazol-1-yl) -1, 2-benziso- thiazol-5-yl] uracil
50 411020 3- [3-[ (4R, 6S) -4, 6-dimethyl-m-dioxan-2- yl] -1, 2-benzisothiazol-5-yl] -1- methyl-6- (trifluoromethyl) uracil
51 411033 3-[3-[(4R,6S)-4,6-dimethyl-m- dioxan-2-yl] -1 , 2-benzisothiazol-
5-yl] -l-methyl-6- (trifluoromethyl) uracil Compound
Number
52 411039 3-[3-(3-chloro-2-thienyl)-l,2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
53 411042 l-methyl-3- [3- (2-thiazolyl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
54 411054 l-methyl-3- [3- (2-methyl-l, 3-dioxolan-2-y 1) -l,2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
55 411099 l-methyl-6- (trifluoromethyl) -3- [3- (4,4, 6-trimethyl-m-dioxan-2-yl) -1,2- benzisothiazol-5-yl] uracil
56 411100 l-methyl-3- [3- (4,4,5, 5-tetra- methyl-1, 3-dioxolan-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
57 411101 l-methyl-3- [3- (4-methyl-l, 3-dioxolan-2-y 1) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
58 411137 2, 4 (1H,3H) -pyrimidinedione, l-methyl-3- [3- (5-methylene-m-dioxan-2-yl) -1, 2-benz - isothiazol-5-yl] -6- (trifluoromethyl) -
59 411152 l-methyl-3- [3- (4-methylpyrazol-l-yl) - 1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
60 411172 3- [3- (2-furyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
61 411188 3- [3- (l,3-dioxolan-2-yl) -6-fluoro-1, 2-be nzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
62 411193 3- (3-m-dioxan-2-yl-6-fluoro-1, 2-benziso- thiazol-5-yl) -l-methyl-6- (trifluoromethyl) uracil
63 411195 3- [3- [(4R,r%) -4, 5-dimethyl-l, 3-dioxolan-
2-yl] -6-fluoro-1, 2-benzisothiazol-
5-yl] -l-methyl-6- (trifluoromethyl) uracil Compound
Number
64 411201 3- [3- [4- (methoxymethyl) -1, 3-dioxolan -2-yl] -1, 2-benzisothiazol-5-yl] -1- methyl-6- (trifluoromethyl) uracil
65 411206 3- [3- (3 , 6-dihydro-4 , 6 , 6-trimethyl-2H-py- ran-2-yl) -1, 2-benzisothiazol-5-yl] - l-methyl-6- (trifluoromethyl) uracil
66 411225 3- [3- [ (4R, 5S-) -4 , 5-dimethyl-l, 3-dioxolan -2-yl] -6-fluoro-1, 2-benzisothiazol- 5-yl] -l-methyl-6- (trifluoromethyl)uracil
67 411228 3- [3- [ (4R, 6S) -4 , 6-dimethyl-m-dioxan- 2-yl] -6-fluoro-1, 2-benzisothiazol- 5-yl] -l-methyl-6- (trifluoromethyl) uracil
68 411233 2,4 (IH, 3H) -pyrimidinedione, l-methyl-3- [3- (2-methyl-3-thienyl) -1, 2-b enzisothiazol-5-yl] -6- (trifluoromethyl) -
69 411325 3- [3- [5- (bromomethyl) -5-hydroxy- m-diaxan-2-yl] -1, 2-benzisothiazol-5- yl] -l-methyl-6- (trifluoromethyl) uracil
70 411382 l-methyl-3- (3-spiro [m-dioxane-5 , 2 ' - oxiran] -2-yl-l, 2-benzisothiazol-5-yl) - 6- (trifluoromethyl) uracil
71 411392 3- [3- (4 , 4-dimethyl-5-oxo-l, 3-dioxolan-2- yl) -1, 2-benzisothiazol-5-yl] - l-methyl-6- (tri luoromethyl) uracil
72 411526 3- [3- [4- (chloromethyl) -1, 3-dioxolan- 2-yl] -1, 2-benzisothiazol-5-yl] -1- methyl-6- (trifluoromethyl) uracil
73 411532 3- [3- [4- (hydroxymethyl) -1, 3-dioxolan- 2-yl] -1, 2-benzisothiazol-5-yl] -1- methyl-6- (trifluoromethyl) uracil
74 411534 3- [3- (4-isoproρyl-2-oxazolin-2-yl) - 1, 2-benzisothiazol-5-yl] -1- methyl-6- (trifluoromethyl) uracil
75 411535 l-methyl-3- [3 (2-oxazolin-2-yl) -1, 2-benz - isothiazol-5-yl] -6- (trifluoromethyl) uracil Compound
Number
76 411557 l-methyl-6- (trifluoromethyl) -3-
[3- (4-vinyl-l, 3-dioxolan-2-yl) -1, 2-benz - isothiazol-5-yl] uracil
77 411558 l-methyl-3- [3- (4-propyl-l, 3-dioxolan-2-y
1) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
78 411560 l-methyl-3- [3- (4-phenyl-l, 3-dioxolan-2-y
1) -l,2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
79 411571 3~[3-[4-(bromethyl)-l,3-dioxolan-
2-yl] -1, 2-benzisothiazol-5-yl] -1- methyl-6- (trifluoromethyl) racil
80 411623 3- [3- [3- (bromomethl) -2-thienyl] -
1, 2-benzisothiazol-5-yl] -1-methyl- 6- (trifluoromethyl) racil
81 411624 3- [3- [3- (methoxymethyl) -2-thienyl] -
1, 2-benzisothiazol-5-yl] -1- methyl-6- (trifluoromethyl) uracil
82 411625 3- [3- (3 , 4-dimethyl-2-thienyl) -1, 2-benz - isothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
83 411626 3- [3- (3-furyl) -1, 2-benzisothiazol-
5-yl] -l-methyl-6- (trifluoromethyl) uracil
84 411872 l-methyl-3- [3- [4- [ ( ethylthio) ethyl] -
1, 3-dioxolan-2-yl] -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
85 411875 3- [3- [3- (hydroxymethyl) -2-thienyl] -
1, 2-benzisothiazol-5-yl] - l-methyl-6- (trifluoromethyl) racil
86 411945 l-methyl-3- [3- [4- [ (methylsulfonyl)methyl] -1, 3-dioxolan-2-yl] -1, 2- benzisothiazol-5-yl] -6- (trifluoromethyl) racil Compound
Number
87 411946 l-methyl-3- [3- [4- [ (methylsulfonyl)methyl] -l,3-dioxolan-2-yl] -1,2- benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
88 411947 l-methyl-3- [3- [4- [ (methylsul- finl) methyl] -l,3-dioxolan-2-yl] -1, 2-benz - isothiazol-5-yl] -6- (trifluoromethyl) racil
89 429142 [2- [5- [3 , 6-dihydro-3-methyl-2 , 6- dioxo-4- (trifluoromethyl) -1 (2H) - pyrimidinyl] -l,2-benzisothiazol-3-l] - l,3-dioxolan-4-yl] methyl thiocyanate
90 429143 3- [3- (3 , 4-dihydro-3-oxo-2-quinoxali- nyl) -l,2-benzisothiazol-5-yl] -1- methyl-6- (trifluoromethyl) racil
91 429144 5- [5- [3, 6-dihydro-3-methyl-2 , 6-dioxo- 4- (trifluoromethyl) -1 (2H) -pyrimidinyl] - 1, 2-benzisothiazol-3-yl] -1, 6-hydro- 6-OXO-2 , 3-pyrazinedicarbonitrile
92 429146 l-methyl-3- [3- (4-oxo-delta-2-l, 2, 5-thia - diazolin-3-yl) -1, 2-benzisothiazol-5-yl] - 6- (trifluoromethyl) uracil S' , S' -dioxide
93 429450 3- [3- [2- (dimethylamino) -4-methoxy-5- oxo-2-imidazolin-4-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
94 429497 3- [3- (4-hydroxy-5-oxo-2-phenyl-2-imidazo lin-4-yl) -1, 2-benzisothiazol-5-yl] - l-methyl-6- (trifluoromethyl) uracil
95 429498 3- [3- (2-tert-butyl-4-hydroxy-5-oxo-2- imidazolin-4-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
96 429499 3-[3-(-hydroxy-5-imino-4,4-dimethyl-2-ox o-3-pyrrolidinyl) -1, 2-benziso - thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil Compound
Number
97 429656 3- [3 [4-methoxy-2- (methylimino) -5-oxo- 4-imidazolidinyl] -1, 2-benzisothiazol- 5-yl] -l-methyl-6- (trifluoromethyl) uracil
98 429657 3- [3 [4-methoxy-2- (ethylimino) -5-oxo-4- imidazolidinyl] -1,2-benzisothiazol- 5-yl] -l-methyl-6- (trifluoromethyl) uracil
EXAMPLE 88
Preemergence herbicidal evaluation of test compounds
The preemergence herbicidal activity of the test compounds of the present invention is exemplified by the following tests in which the seeds of a variety of monocotyledonous and dicotyledonous plants are separately mixed with potting soil and planted on top of approximately one inch of soil in separate pint cups. After planting, the cups are sprayed with the selected aqueous acetone solution containing test compound in sufficient quantity to provide the equivalent of about 0.0156 to 0.500 kg per hectare of test compound per cup. The treated cups are then placed on greenhouse benches, watered and cared for in accordance with conventional greenhouse procedures. From four to five weeks after treatment, the tests are terminated and each cup is examined and rated according to the rating system provided in Example 87.
The data obtained are reported in Table II below. The compounds evaluated are reported by compound number given in Example 87.
Compound Number 1 397688 l-methyl-3- [3- (3-thienyl) -1, 2-benziso - thiazol-5-yl] -6- (trifluoromethyl) uracil
2 397753 ethyl (R)-2-[5-[3,6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1,2-benziso- thiazol-3-yl] -4-thiazolidinecarboxylate
397828 l-methyl-3- [3- (2-thienyl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
397830 l-methyl-3- [3- (3-methyl-2-thienyl) -1,2- benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
397903 l-methyl-3- [3- (1-methyl- imidazol-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
399079 l-methyl-3- [3- (1-methyl- pyrrol-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
399086 l-methyl-3- [3- (4-methyl-2-thiazolyl) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
8 399179 3- [3- (2, 5-diethyl-3-thienyl) -1, 2-benz - isothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
9 399270 l-methyl-3- [3- (2-pyrodyl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) racil
10 399343 3- [3- (3-methoxy-2-thienyl) -1, 2-benziso - thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
11 399425 l-methyl-3- [3- (3-pyridyl) -1, 2-benziso - thiazol-5-yl] -6- (trifluoromethyl) uracil
12 399517 l-methyl-3- [3- (2-pyrimidinyl) -1, 2-benz - isothiazol-5-yl] -6- (trifluoromethyl) uracil
13 399537 3-[3-[ (1R,2S)-1, 2-epoxypropyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
14 399538 3- [3-[ (1R,2R)-1, 2-epoxypropyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
15 399566 l-methyl-3- [3- (2-pyridyl) -1, 2-benziso - thiazol-5-yl] -6- (trifluoromethyl) uracil N' ' ,S,S-trioxide Compound Number
16 399653 l-methyl-3- [3- (5-methyl-l, 3,4-oxadiazol -2-yl) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
17 399741 l-methyl-3- [3- (5-methyl-l, 3, 4-thiadiazo 1-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
18 399753 l,2-benzisothiazole-3-carboxanilide, 4 ' -chloro-5- [3 , 6-di - hydro-3-methy1-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -N-methyl-
19 399766 l-methyl-3- [3- (3-methyl-2-pyridyl) -1,2- benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
20 399854 N- [3- (5-methyl-2-thienyl) -1,2-benziso- thiazol-5-yl] -1-cyclohexene-l, 2-dicar- boximide
21 399855 l-methyl-3- [3- (5-methyl-2-thienyl) -1,2- benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
22 399857 Methyl [ (2- [5- [3 , 6-di- hydro-3-methyl-2,6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benziso- thiazol-3-yl] -3-thienyl] oxy] acetate
23 399858 methyl 2- [ (2- [5- [3, 6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1,2-benziso- thiazol-3-yl] -3-thienyl] oxy]propionate
24 410061 3- [3- (1, 3-dithiolan-2-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
25 410062 3- [6-fluoro-3- (2-pyridyl) -1,2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
26 410095 l-methyl-3- [3- (4-methyl-3-thienyl) -1,2- benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
27 410111 3- [3- (3 , 5-dimethyl-2-thienyl) -1 , 2-benz - isothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
28 410115 3- (3-m-dioxan-2-yl-l, 2-benziso- thiazol-5-yl) -l-methyl-6- (trifluoro¬ methyl) uracil
29 410116 3-acetyl-2- [5- [3 , 6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benziso- thiazol-3-yl] thiazolidine Compound Number
30 410122 3-benzoyl-2- [5- [3,6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benziso- thiazol-3-yl] thiazolidine
31 410143 l-methyl-3- [3- (1, 3-oxa- thiolan-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) racil
32 410223 l-methyl-3- [3- (1, 3-oxa- thioln-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil S' , S' -dioxide
33 410225 1, 2-benzisothiazole-3-carboxaldehyde, 5-[3,6-di- hydro-3-methyl-2 , 6-dioxo-4- (trifluoro- methyl) -1 (2H) -pyrimidinyl] -, 3- [bis (2-hydroxyethyl) dithioacetal]
34 410275 l-methyl-3- [3- (1, 3-oxa- thian-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
35 410290 l-methyl-3- [3- (1, 3-oxa- thian-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil S' , S' -dioxide
36 410291 3- [3 (5, 5-dimethy1-m- dioxan-2-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
37 410309 l-methyl-3- [3- (4-methyl-m- dioxan-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) racil
38 410312 l-methyl-3- [3- (3-methyl- pyrazol-1-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethi) uracil
39 410384 2-propynyl [ [2- [5- [3, 6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benziso- thiazol-3-yl] -3-thienyl] oxy] acetate
40 410399 3- [3- (4, 6-dimethyl-2-pyrimidinyl) -1,2-b enzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
41 410228 3- [3- (3-methoxy-2-pyridyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
42 410504 l-methyl-3- [3- (5-methyl-2-pyridyl) -1,2- benzisothiazol-5-yl] -6- (trifluoromethyl) uracil Compound Number
43 410597 3- [3- (4, 6-diethoxy-2-pyrimidinyl) -1,2-b enzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
44 410815 3- [6-fluoro-3- (3-methyl-2-pyridyl) -1, 2- benzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
45 410850 3- [3- (1, 3-dioxolan-2-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
46 410875 N- [6-fluoro-3- (3-methyl-2-pyridyl)-l,2- benzisothiazol-5-yl] -1-cyclohex- ene-l,2-dicarboximide
47 411010 3- [3- [ (4R, 5S) -4 , 5-dimethyl-l, 3-dioxolan -2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
48 411011 3- [3- [(4R,5R) -4, 5-dimethyl-l, 3-dioxolan -2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
49 411019 l-methyl-6- (trifluoromethyl) -3- [3- (3, 4, 5-trimethylpyrazol-l-yl) -1, 2-benziso - thiazol-5-yl] uracil
50 411020 3- [3-[ (4R,6S)-4,6-dimethyl-m- dioxan-2-yl] -1, 2-benziso - thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
51 411033 3- [3- [ (4R, 6S) -4, 6-dimethy1-m- dioxan-2-yl] -1, 2-benziso - thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
52 411039 3- [3- (3-chloro-2-thienyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
53 411042 l-methyl-3- [3- (2-thiazolyl) -1, 2-benz - isothiazol-5-yl] -6- (trifluoromethyl) uracil
54 411054 l-methyl-3- [3- (2-methyl-l, 3-dioxolan-2- yl) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
55 411099 l-methyl-6- (trifluoromethyl) -3- [3- (4 , 4 , 6-trimethyl-m- dioxan-2-yl) -1, 2-benziso - thiazol-5-yl] uracil
56 411100 l-methyl-3- [3- (4 , 4 , 5 , 5-tetra- methyl-1, 3-dioxolan-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil Compound Number
57 411101 l-methyl-3- [3- (4-methyl-l, 3-dioxolan-2- yl) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
58 411137 2,4 (1H,3H) -pyrimidinedione, l-methyl-3- [3- (5-methylene- m-dioxan-2-yl) -1, 2-benziso - thiazol-5-yl] -6- (trifluoromethyl) -
59 411152 l-methyl-3- [3- (4-methyl- pyrazol-1-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) racil
60 411172 3- [3- (2-furyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil 61 411188 3- [3- (l,3-dioxolan-2-yl) -6-fluoro-1, 2-b enzisothiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
62 411193 3- (3-m-dioxan-2-yl-6-fluoro-1, 2-benz - isothiazol-5-yl) -l-methyl-6- (trifluoromethyl) uracil
63 411195 3- [3- [ (4R, r%) -4 , 5-dimethyl-l, 3-dioxolan -2-yl] -6-fluoro-1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
64 411201 3- [3- [4- (methoxymethyl) -1, 3-dioxolan-2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
65 411206 3- [3- (3, 6-dihydro-4, 6, 6-trimethyl-2H- pyran-2-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
66 411225 3- [3- [ (4R, 5S-) -4 , 5-dimethyl-l, 3-dioxola n-2-yl] -6-fluoro-1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
67 411228 3- [3- [ (4R,6S)-4,6-dimethyl-m- dioxan-2-yl] -6-fluoro-1, 2-benziso - thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
68 411233 2, 4 (1H,3H) -pyrimidinedione, l-methyl-3- [3- (2-methyl-3-thienyl) -1, 2- benzisothiazol-5-yl] -6- (trifluoromethyl) -
69 411325 3- [3- [5- (bromomethyl) -5-hydroxy- m-diaxan-2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil Compound Number
70 411382 l-methyl-3- (3-spiro [m-diox- ane-5 , 2 ' -oxiran] -2-yl-l, 2-benziso- thiazol-5-yl) -6- (trifluoromethyl) uracil
71 411392 3- [3- (4,4-dimethyl-5-oxo-l,3-dioxolan-2 -yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
72 411526 3- [3- [4- (chloromethyl) -l,3-dioxolan-2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
73 411532 3- [3- [4- (hydroxymethyl) -1, 3-dioxolan-2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
74 411534 3- [3- (4-isopropyl-2-oxa- zolin-2-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
75 411535 l-methyl-3- [3 (2-oxa- zolin-2-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil
76 411557 l-methyl-6- (trifluoromethyl) -3- [3- (4-vinyl-l, 3-dioxolan-2-yl ) -1, 2-benzisothiazol-5-yl] uracil
77 411558 l-methyl-3- [3- (4-propyl-l, 3-dioxolan-2- yl) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
78 411560 l-methyl-3- [3- (4-phenyl-l, 3-dioxolan-2- yl) -1, 2-benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
79 411571 3-[3-[4-(brom- ethyl) -1, 3-dioxolan-2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
80 411623 3- [3- [3- (bromomethl) -2-thienyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
81 411624 3- [3- [3- (methoxymethyl) -2-thienyl] -1, 2-benziso - thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
82 411625 3- [3- (3, 4-dimethyl-2-thienyl)-l, 2-benz - isothiazol-5-yl] -l-methyl-6- (trifluorome hyl) uracil Compound Number
83 411626 3- [3- (3-furyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) racil
84 411872 l-methyl-3- [3- [4- [ (methyl - thio)methyl] -1, 3-dioxolan-2-yl] -1,2-ben zisothiazol-5-yl] -6- (trifluoromethyl) uracil
85 411875 3- [3- [3- (hydroxymethyl) -2-thienyl] -1,2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
86 411945 l-methyl-3- [3- [4- [ (methylsulfonyl) methyl] -l,3-dioxolan-2-yl] -1,2 -benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
87 411946 l-methyl-3- [3- [4- [ (methylsulfonyl)methyl] -l,3-dioxolan-2-yl] -1,2 -benzisothiazol-5-yl] -6- (trifluoromethyl) uracil
88 411947 l-methyl-3- [3- [4- [ (methylsul- finDmethyl] -l,3-dioxolan-2-yl] -1,2-ben zisothiazol-5-yl] -6- (trifluoromethyl) uracil
89 429142 [2-[5-[3,6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benziso- thiazol-3-1] -l,3-dioxolan-4-yl] methyl thiocyanate
90 429143 3- [3- (3 , 4-dihydro-3-oxo-2-quinoxali - nyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
91 429144 5-[5-[3,6-di- hydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl] -1, 2-benziso - thiazol-3-yl] -1, 6-hydro-6-oxo-2, 3-pyra- zinedicarbonitrile
92 429146 l-methyl-3- [3- (4-oxo- delta-2-1, 2 , 5-thiadiazo- lin-3-yl) -1, 2-benziso- thiazol-5-yl] -6- (trifluoromethyl) uracil S' ,S' -dioxide
93 429450 3- [3- [2- (dimethyl - amino) -4-methoxy-5-oxo-2-imidazolin-4-y 1] -1,2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil Compound Number
94 429497 3- [3- (4-hydroxy-5-oxo-2-phenyl-2-imidaz olin-4-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
95 429498 3-[3-(2-tert-bu- tyl-4-hydroxy-5-oxo-2-imidazolin-4-yl) - 1, 2-benziso - thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
96 429499 3- [3- (-hydroxy-5-imino-4,4-dimethyl-2-o xo-3-pyrrolidinyl) -1, 2-benziso - thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
97 429656 3- [3 [4-methoxy-2- (methyl - i ino) -5-oxo-4-imidazo- lidinyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
98 429657 3- [3 [4-methoxy-2- (ethyl - imino) -5-oxo-4-imidazo- lidinyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl) uracil
Figure imgf000218_0001
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EXAMPLE 89
Rice tolerance to post-transplant applications and preemergence weed control under flooded paddy conditions
The tolerance of transplanted rice to post-transplanted herbicide applications is determined as follows: two ten-day-old rice seedlings (cv. Tebonnet) are transplanted into silt loam soil in 32 oz . plastic containers with a diameter of 10.5 cm and no drainage holes. After transplanting, the containers are flooded and the water level is maintained at 1.5 to 3 cm above the soil surface. Three days after transplanting, the flooded soil surface of the containers is treated with the selected aqueous/acetone 50/50 v/v mixture containing the test compounds to provide the equivalent of about 0.0313 to 0.500 kg/ha of active ingredient. The treated containers are placed on greenhouse benches, watered such that the water level is maintained as stated above, and cared for in accordance with conventional greenhouse procedures. Three to four weeks after treatment, the test is terminated and each container is examined and herbicidal effect rated according to the rating system provided in Example 185. The data obtained are reported in Table III. The compounds evaluated are reported by compound number given in Example 87.
Preemergence herbicidal activity under flooded paddy conditions is determined as follows: plant seeds or propagating organs are planted in the top 0.5 cm of silt loam soil in 32 oz . plastic containers with a diameter of 10.5 cm and no drainage holes. Water is added to these containers and maintained at 1.5 to 3 cm above the soil surface for the duration of the experiment. The test compounds are applied as aqueous/acetone mixtures 50/50 v/v pipetted directly into the flood water to give the equivalent of about 0.0313 to 0.500 kg/ha of active ingredient. The treated containers are placed on greenhouse benches and cared for in accordance with conventional greenhouse procedures. Three to four weeks after treatment, the test is terminated and each container is examined and herbicidal effect rated according to the rating system provided in Example 185. The data obtained are reported in Table III. The compounds evaluated are reported by compound number given in Example 87.
Plant species employed in this example are reported by header abbreviation, common name and scientific name. PLANT SPECIES EMPLOYED IN RICE TOLERANCE/PREEMERGENCE WEED
CONTROL EVALUATIONS
Header Abbr. Common Name Scientific Name
ECHORC Watergrass (Calif.) Echinochloa oryzoides (Ard.) Fritsch.
CYPIR Rice Flatsedge Cyperus iria CYPSE Flatsedge Cyperus serotinus, Rottb. MOOVA Monochoria Monochoria vaginalis, Presl. SAGPY Arrowhead (Pygmaea) Sagittaria pygmaea, L. ORYSAT Rice, Tebonnet Oryza sativa, (L.) Tebonnet
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
E O
C c c M S R
H Y Y O A Y
0 P P 0 G S
Compound Rate R 1 s V P A
Number (kg/ha) C R E A Y T
0.0040 6.0 6.0 0.0 9.0 0.0 1.0
28 0.2500 9.0 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 9.0 9.0 9.0 9.0 9.0
0.0620 9.0 9.0 9.0 9.0 9.0 9.0
0.0320 8.5 9.0 9.0 9.0 8.0 9.0
0.0160 8.0 9.0 9.0 9.0 4.5 9.0
0.0080 5.0 8.0 9.0 0.0 7.0
0.0040 3.0 8.0 9.0 0.0 3.0
0.0020 0.0 0.0 0.0 0.0 0.0
29 0.2500 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 9.0 6.0 9.0 9.0 7.0
0.0620 7.5 7.0 0.0 9.0 4.0 6.0
0.0320 7.0 7.0 0.0 9.0 3.5 3.5
0.0160 4.5 4.5 0.0 7.0 1.5 1.5
0.0080 0.0 0.0 0.0 0.0 0.0
0.0040 0.0 0.0 0.0 0.0 0.0
0.0020 0.0 0.0 0.0 0.0 0.0
30 0.2500 9.0 9.0 6.0 9.0 9.0 7.0
0.1250 9.0 9.0 3.0 9.0 6.0 5.0
0.0620 8.0 9.0 0.0 9.0 2.0 3.5
0.0320 4.0 7.0 0.0 8.5 1.0 3.0
0.0160 3.5 3.0 0.0 4.5 0.0 1.0
0.0080 3.0 0.0 0.0 0.0 0.0
0.0040 0.0 0.0 0.0 0.0 0.0
0.0020 0.0 0.0 0.0 0.0 0.0
31 0.2500 9.0 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 9.0 5.0 9.0 9.0 9.0
0.0620 9.0 9.0 9.0 7.0 9.0
0.0320 8.0 9.0 4.0 9.0 9.0 7.5
0.0160 6.0 9.0 0.0 9.0 6.0 5.5
0.0080 3.0 0.0 5.0 0.0 0.0
0.0040 3.0 0.0 0.0 0.0 0.0
0.0020 0.0 0.0 0.0 0.0 0.0
32 0.2500 3.0 9.0 9.0 9.0 6.0
0.1250 0.0 7.0 9.0 3.0
0.0620 0.0 4.0 4.0 6.0 0.0
0.0320 0.0 4.0 0.0 6.0 0.0
0.0160 0.0 3.0 0.0 4.0 0.0
33 0.2500 7.0 6.0 0.0 5.0 3.0
0.1250 2.0 3.0 0.0 4.0 1.0
0.0620 0.0 0.0 0.0 0.0 0.0
0.0320 0.0 0.0 0.0 0.0 0.0 E O
C c C M S R
H Y Y 0 A Y
0 P P 0 G S
Compound Rate R 1 s V P A
Number (kg/ha) C R E A Y T
0.0160 0.0 0.0 0.0 0.0 0.0
34 0.2500 9.0 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 7.5 9.0 9.0 6.0 9.0
0.0620 8.0 7.0 9.0 9.0 3.5 8.5
0.0320 7.5 6.0 9.0 7.5 3.5 4.0
0.0160 4.5 2.5 0.0 7.5 1.5 3.5
0.0080 5.0 0.0 0.0 0.0 3.0
35 0.2500 9.0 9.0 9.0 9.0 9.0 8.0
0.1250 7.5 9.0 5.0 9.0 8.0 7.5
0.0620 7.0 9.0 3.0 9.0 5.0 5.5
0.0320 5.5 6.0 2.0 5.0 4.5 4.0
0.0160 4.0 1.5 0.0 0.0 2.5 1.0
0.0080 0.0 0.0 0.0 0.0 0.0
36 0.2500 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 9.0 9.0 9.0 9.0
0.0620 9.0 9.0 9.0 9.0 7.0 9.0
0.0320 8.5 9.0 9.0 9.0 3.5 7.5
0.0160 8.0 6.5 9.0 9.0 0.0 6.0
0.0080 5.0 0.0 9.0 0.0 5.0
0.0040 3.0 0.0 5.0 0.0 3.0
0.0020 3.0 0.0 0.0 0.0 0.0
37 0.2500 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 9.0 9.0 9.0 9.0
0.0620 9.0 9.0 9.0 9.0 9.0 9.0
0.0320 9.0 9.0 9.0 9.0 7.0 8.5
0.0160 9.0 9.0 9.0 9.0 7.0 8.5
0.0080 3.0 0.0 3.0 0.0 5.0
0.0040 3.0 0.0 0.0 0.0 3.0
0.0020 3.0 0.0 0.0 0.0 0.0
38 0.2500 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 9.0 9.0 9.0 9.0
0.0620 8.5 9.0 9.0 9.0 4.5 7.0
0.0320 7.0 9.0 9.0 9.0 4.5 3.5
0.0160 6.0 8.0 9.0 9.0 4.5 3.0
0.0080 0.0 3.0 3.0 0.0 0.0
0.0040 0.0 0.0 0.0 0.0 0.0
0.0020 0.0 0.0 0.0 0.0 0.0
39 0.2500 0.0 5.0 0.0 9.0 7.0 3.0
0.1250 0.0 5.0 0.0 9.0 3.0 4.0
0.0620 0.0 4.0 0.0 9.0 0.0 2.0
0.0320 0.0 5.0 0.0 9.0 0.0 0.0
0.0160 0.0 5.0 0.0 9.0 0.0 0.0 E O
C C C M s R
H Y Y O A Y
0 P P 0 G S
5 Compound Rate R 1 s V P A
Number (kg/ha) C R E A Y T
40 0.2500 7.0 7.0 0.0 9.0 5.0 7.0
0.1250 6.0 6.0 0.0 9.0 5.0 7.0
0.0620 4.0 5.0 0.0 9.0 3.0 4.0 o 0.0320 2.0 5.0 0.0 7.0 0.0 5.0
0.0160 0.0 0.0 0.0 6.0 0.0 5.0
41
42 0.2500 7.0 9.0 2.0 9.0 6.0 4.0
0.1250 6.0 6.0 0.0 9.0 3.0 4.0
3 — 0.0620 4.0 4.0 0.0 9.0 0.0 6.0
0.0320 2.0 3.0 0.0 8.0 0.0 3.0
0.0160 0.0 0.0 0.0 6.0 0.0 2.0
43 0.2500 9.0 5.0 0.0 9.0 3.0 4.0
0.1250 9.0 5.0 0.0 6.0 2.0 2.0
0.0620 9.0 3.0 0.0 6.0 0.0 1.0
0 0.0320 5.0 0.0 0.0 4.0 0.0 0.0
0.0160 2.0 0.0 0.0 3.0 0.0 0.0
44 0.2500 9.0 9.0 9.0 9.0 9.0 8.0
0.1250 9.0 9.0 9.0 9.0 9.0 7.5
0.0620 9.0 9.0 9.0 8.5 8.0 7.5
5 0.0320 8.5 8.0 9.0 8.5 4.5 7.5
0.0160 8.5 3.5 0.0 3.0 2.5 3.0
0.0080 3.0 0.0 0.0 0.0 0.0 0.0
45 0.2500 9.0 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 9.0 9.0 9.0 9.0 9.0
0 0.0620 8.3 9.0 9.0 9.0 9.0 9.0
0.0320 7.3 9.0 9.0 9.0 8.0 9.0
0.0160 6.0 9.0 9.0 9.0 7.7 9.0
0.0080 3.5 9.0 9.0 4.5 7.0 8.5
0.0040 3.0 0.0 5.0 3.0 7.0
5 46 0.2500 7.0 3.0 3.0 7.0 3.0 4.0
0.1250 7.0 3.0 0.0 7.0 2.0 3.0
0.0620 6.0 2.0 0.0 7.0 0.0 3.0
0.0320 5.0 1.0 7.0 0.0 2.0
0.0160 4.0 0.0 0.0 7.0 0.0 1.0 0 47 0.2500 9.0 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 9.0 9.0 9.0 9.0 9.0
0.0620 8.5 9.0 9.0 9.0 8.0 9.0
0.0320 8.5 8.5 9.0 9.0 7.5 7.5
0.0160 8.5 5.0 3.0 9.0 2.5 7.0 ς 0.0080 5.0 0.0 0.0 3.0
48 0.2500 9.0 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 9.0 9.0 9.0 9.0 9.0 LO LO t iπ σ in o in o to in σ in
Figure imgf000276_0001
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Figure imgf000277_0001
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Figure imgf000278_0001
E O
C C C S R
H Y \ O A Y
O P P O G S
Compound Rate R 1 S ; v P A
Number (kg/ha) C R E A Y T
68 0.2500 9.0 9.0 9.0 9.0 4.0
0.1250 9.0 9.0 9.0 9.0 3.5
0.0620 9.0 9.0 9.0 8.5 3.0
0.0320 8.5 9.0 9.0 0.0 2.5
0.0160 7.0 3.5 7.0 0.0 1.5
0.0080 7.0 0.0 7.0 0.0 1.5
69 0.2500 3.0 9.0 9.0 9.0 3.0
0.1250 3.0 3.0 3.0 3.0 3.0
0.0620 3.0 3.0 3.0 0.0 0.0
0.0320 0.0 0.0 0.0 0.0 0.0
0.0160 0.0 0.0 0.0 0.0 0.0
0.0080 0.0 0.0 0.0 0.0 0.0
70 0.2500 3.0 3.0 3.0 9.0 3.0
0.1250 0.0 0.0 0.0 0.0 0.0
0.0620 0.0 0.0 0.0 0.0 0.0
0.0320 0.0 0.0 0.0 0.0 0.0
0.0160 0.0 0.0 0.0 0.0 0.0
0.0080 0.0 0.0 0.0 0.0 0.0
71 0.2500 3.0 5.0 5.0 0.0 3.0
0.1250 0.0 0.0 0.0 0.0 0.0
0.0620 0.0 0.0 0.0 0.0 0.0
0.0320 0.0 0.0 0.0 0.0 0.0
0.0160 0.0 0.0 0.0 0.0 0.0
0.0080 0.0 0.0 0.0 0.0 0.0
72 0.2500 9.0 9.0 9.0 9.0 8.0
0.1250 9.0 9.0 9.0 8.0 8.0
0.0620 9.0 9.0 9.0 9.0 8.0
0.0320 9.0 3.0 9.0 0.0 7.0
0.0160 9.0 0.0 5.0 0.0 5.0
0.0080 5.0 0.0 0.0 0.0 0.0
73 0.2500 8.0 9.0 9.0 9.0 7.0
0.1250 7.0 9.0 9.0 3.0 5.0
0.0620 3.0 3.0 3.0 0.0 3.0
0.0320 0.0 0.0 0.0 0.0 0.0
0.0160 0.0 0.0 0.0 0.0 0.0
0.0080 0.0 0.0 0.0 0.0 0.0
74 0.2500 9.0 9.0 9.0 9.0 6.0
0.1250 9.0 9.0 9.0 7.0 6.0
0.0620 9.0 6.0 9.0 1.5 4.5
0.0320 8.0 6.0 9.0 1.5 4.0
0.0160 6.5 0.0 9.0 0.0 3.5
0.0080 5.5 0.0 4.5 0.0 1.5 E O
C C C M s R
H Y Y O A Y
O P P O G S
5 Compound Rate R I S V P A
Number (kg/ha) C R E A Y T
75 0.2500 9.0 9.0 9.0 9.0 6.0
0.1250 8.5 9.0 9.0 9.0 6.0
0.0620 8.0 9.0 9.0 7.0 6.0 o 0.0320 4.0 7.0 7.0 4.5 4.5
0.0160 2.5 1.5 6.0 4.5 2.5
0.0080 1.5 0.0 0.0 0.0 2.5
76 0.2500 9.0 9.0 9.0 9.0 9.0
0.1250 9.0 9.0 9.0 9.0 9.0 c
0 0.0620 9.0 9.0 9.0 5.0 8.0
0.0320 7.0 8.0 9.0 0.0 3.0
0.0160 5.0 8.0 9.0 0.0 3.0
0.0080 5.0 7.0 9.0 0.0 2.0
77 0.2500 9.0 9.0 9.0 9.0 8.0
0.1250 9.0 9.0 9.0 5.0 7.0
0 0.0620 8.0 9.0 9.0 0.0 3.0
0.0320 5.0 7.0 9.0 0.0 3.0
0.0160 5.0 7.0 9.0 0.0 0.0
0.0080 0.0 0.0 0.0 0.0 0.0
78 0.2500 9.0 9.0 9.0 9.0 8.5
5 0.1250 9.0 9.0 9.0 9.0 8.5
0.0620 9.0 9.0 9.0 4.5 7.0
0.0320 9.0 9.0 9.0 1.0 5.7
0.0160 8.3 7.0 7.7 0.0 4.7
0.0080 8.0 0.0 7.7 0.0 4.0
0 0.0040 4.0 8.0 0.0 7.0
0.0020 2.0 8.0 0.0 2.0
79 0.2500 9.0 9.0 9.0 9.0 8.0
0.1250 9.0 9.0 9.0 3.0 7.0
0.0620 9.0 9.0 9.0 3.0 7.0
5 0.0320 8.0 3.0 9.0 0.0 5.0
0.0160 6.0 0.0 0.0 0.0 2.0
0.0080 0.0 0.0 0.0 0.0 0.0
80 0.2500 8.5 9.0 9.0 9.0 8.5
0.1250 8.0 9.0 9.0 7.0 8.0
0 0.0620 6.0 7.0 9.0 4.5 8.0
0.0320 4.0 4.5 9.0 4.5 5.5
0.0160 1.5 0.0 4.5 0.0 5.0
0.0080 1.0 0.0 0.0 0.0 2.5
81 0.2500 9.0 9.0 9.0 9.0 8.5 ς 0.1250 9.0 9.0 9.0 9.0 8.0
0.0620 9.0 9.0 9.0 7.0 8.0
0.0320 9.0 9.0 9.0 4.7 6.7 E O
C c c M S R
H Y Y O A Y
O P P O G S
Compound Rate R 1 s V P A
Number (kg/ha) C R E A Y T
0.0160 8.7 9.0 9.0 1.0 6.3
0.0080 8.0 7.0 7.7 0.0 5.0
0.0040 6.0 9.0 0.0 7.0
0.0020 2.0 8.0 0.0 7.0
82 0.2500 9.0 9.0 9.0 9.0 7.0 6.0
0.1250 9.0 9.0 9.0 9.0 3.5 3.5
0.0620 9.0 9.0 9.0 9.0 1.0 2.0
0.0320 9.0 9.0 9.0 9.0 0.0 2.0
0.0160 8.0 8.5 9.0 0.0 1.0
0.0080 7.0 6.5 8.5 0.0 0.5
83 0.2500 8.0 9.0 9.0 3.0 5.0
0.1250 7.0 3.0 9.0 0.0 2.0
0.0620 7.0 0.0 9.0 2.0
0.0320 6.0 0.0 9.0 0.0 2.0
0.0160 5.0 0.0 5.0 0.0 1.0
0.0080 0.0 0.0 0.0 0.0 0.0
84 0.2500 9.0 9.0 9.0 4.5 7.0
0.1250 8.0 6.0 9.0 4.0 5.5
0.0620 7.0 2.5 9.0 0.0 4.0
0.0320 7.5 1.5 9.0 0.0 1.5
0.0160 1.5 0.0 4.5 0.0 1.5
0.0080 0.0 0.0 9.0 0.0 0.0
85 0.2500 9.0 9.0 9.0 9.0 8.5
0.1250 8.0 6.0 9.0 7.0 5.5
0.0620 6.5 5.0 9.0 , 4.5 4.0
0.0320 5.0 0.0 7.0 1.5 1.5
0.0160 0.0 0.0 4.5 0.0 0.0
0.0080 0.0 0.0 9.0 0.0 0.0
86 0.2500 5.0 3.0 9.0 0.0 8.0
0.1250 3.0 0.0 9.0 0.0 5.0
0.0620 0.0 0.0 9.0 0.0 3.0
0.0320 0.0 0.0 5.0 0.0 0.0
0.0160 0.0 0.0 0.0 0.0 0.0
87 0.2500 0.0 9.0 9.0 5.0 5.0
0.1250 0.0 5.0 8.0 0.0 3.0
0.0620 0.0 0.0 8.0 0.0 0.0
0.0320 0.0 0.0 0.0 0.0 0.0
0.0160 0.0 0.0 0.0 0.0 0.0
88 0.2500 0.0 9.0 9.0 5.0 8.0
0.1250 0.0 9.0 9.0 0.0 5.0
0.0620 0.0 5.0 5.0 0.0 3.0
0.0320 0.0 0.0 0.0 0.0 0.0 co co to t H1 in σ in σ in o in o in
OO bb θD θ
M M O O
o eπ bb
o o b b
o o bb
p p bb pi b
Figure imgf000282_0001
EXAMPLE 90
Rice tolerance to post-transplant applications and postemergence weed control under flooded paddy conditions
Plastic containers containing weeds which are 3 to 5 cm tall and rice seedlings at the 1.5 to 2.5 leaf stage are flooded with water. The water is maintained at 1.5 to 3 cm above the soil surface for the duration of the experiment. Test compounds are applied as aqueous/acetone mixtures 50/50 v/v directly into the flood water to provide the equivalent of about 0.0313 to 0.500 kg/ha of active ingredient. The treated containers are placed on greenhouse benches and cared for in accordance with conventional greenhouse procedures. Three to four weeks after treatment, the test is terminated and each container is examined and herbicidal effect rated according to the rating system provided in Example 185. The results are summarized in Table IV. The compounds evaluated are reported by compound number given in Example 87.
Table IV
PADDY CONDITIONS - POST-TRANSPLANT RICE
POSTEMERGENCE WEEDS
E O
C c c M s R
H Y Y O A Y
O P P O G s Compound Rate R 1 s V P A
Number (kg/ha) C R E A Y T
1 0.2500 9.0 9.0 9.0 9.0 9.0 8.0
0.1250 9.0 9.0 7.0 9.0 9.0 7.0
0.0620 9.0 9.0 4.0 9.0 7.0 7.0
0.0320 9.0 9.0 2.0 9.0 4.0 7.0
0.0160 7.0 9.0 0.0 9.0 2.0 6.0
0.0080 4.0 9.0 0.0 9.0 0.0 4.0
8 0.2500 5.5 9.0 0.0 9.0 2.0 3.5
0.1250 5.0 9.0 0.0 5.5 1.0 2.0
0.0620 4.0 9.0 0.0 4.5 0.0 2.0
0.0320 3.5 9.0 0.0 4.5 0.0 1.0
0.0160 2.0 9.0 0.0 4.5 0.0 1.0
0.0080 1.0 4.5 0.0 4.5 0.0 0.5 12 0.2500 2.0 9.0 0.0 4.0 0.0 4.0
0.1250 1.0 9.0 0.0 2.0 0.0 2.0
0.0620 0.0 7.0 0.0 1.0 0.0 2.0
0.0320 0.0 2.0 0.0 0.0 0.0 2.0
21 0.2500 9.0 9.0 0.0 9.0 0.0 7.0
0.1250 9.0 9.0 0.0 9.0 0.0 7.0
0.0620 9.0 9.0 0.0 9.0 0.0 7.0
0.0320 6.0 9.0 0.0 9.0 0.0 4.0
0.0160 4.0 9.0 0.0 9.0 0.0 3.0
0.0080 0.0 8.0 0.0 9.0 0.0 3.0 22 0.1250 0.0 0.0 0.0 0.0 0.0 0.0
0.0620 0.0 0.0 0.0 0.0 0.0 0.0
0.0320 0.0 0.0 0.0 0.0 0.0 0.0
0.0160 0.0 0.0 0.0 0.0 0.0 0.0
0.0080 0.0 0.0 0.0 0.0 0.0 0.0
0.0040 0.0 0.0 0.0 0.0 0.0 0.0
26 0.1250 9.0 9.0 7.0 6.0 0.0 6.0
0.0620 9.0 9.0 7.0 4.0 0.0 5.0
0.0320 7.0 9.0 7.0 4.0 0.0 4.0
0.0160 4.0 8.0 4.0 2.0 0.0 3.0
0.0080 2.0 0.0 2.0 0.0 2.0
0.0040 0.0 0.0 0.0 0.0 2.0 10 > to to in o in o in o in in
Figure imgf000285_0001
Figure imgf000285_0002
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p p po CO CD CD o co o o o co oo co sJ CO O O O O O -ϋ".
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p p p p popo ppcD pp p ro^ ^ pp pp wco o po rocoppr co cD co bbbbbbbbbbbbbbbbbbbb bbbbbbbbbbbbbbbb
p p p p p p p p cD co cop pop p t pp ppppppo 0. 04i» 000000
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Claims

WHAT IS CLAIMED IS:
A compound of formula I
Figure imgf000286_0001
wherein
Q is selected from
Figure imgf000286_0002
Q9 ,10 nil .12
Figure imgf000287_0001
Figure imgf000287_0002
Q26 Q27 Q28
Figure imgf000287_0003
Q29 Q30 Q31 Q32
Figure imgf000288_0001
R is halogen, Cι-C6-alkyl, Cι-C6-haloalkyl, C3-C7-cyclo- alkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C3-Cg-al- kynyl, cyano, benzyl, hydroxyl, amino, C2-Cg-cyano- alkyl and when R and R1 are taken together with the other atoms to which they are attached, they represent a four to seven-membered ring optonally interrupted by oxygen, sulfur or nitrogen and optionally substituted with one to three methyl groups or one or more halogen atoms;
Rl is hydrogen, halogen, Cι-C6-alkyl, Cι-C6-haloalkyl,
C3-C7-cycloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C3-Cg-alkynyl, cyano, benzyl, hydroxyl, amino, C2-C6- cyanoalkyl and when R and Rl are taken together with the other atoms to which they are attached, they represent a four to seven-membered ring optionally interrupted by oxygen, sulfur or nitrogen and optionally substituted with one to three methyl groups or one or more halogen atoms;
R2 and R3 are each independently hydrogen, halogen, Ci-Cg- alkyl, Cι-C6-haloalkyl, C3-C-cycloalkyl, C2-C6-al- kenyl, C2-C6-haloalkenyl, C3-Cg-alkynyl, OR8, S(0)m-R9 or Ri°Riι and when R2 and R3 are taken together with the atoms to which they are attached, they represent a four to seven-membered saturated or unsaturated ring optionally interupted by oxygen, sulfur or nitrogen and optionally substituted with one to three methyl groups or one or more halogen atoms; R4, R6 and R7 are each independently hydrogen, halogen or Cι-C6-alkyl;
R5 is hydrogen, halogen, Cι-C6-alkyl, Ci-Cδ-haloalkyl, C3-C7-cycloalkyl, C3-C6~alkenyl, C -C6-haloalkenyl,
C3-C6-alkynyl, ORi2 or SRl3;
R8, R9, Ri2, Rl3 and Ri4 are each independently hydrogen, Cι-C- alkyl, Cι-C4-haloalkyl, C2-C6-alkenyl, C2-C6-halo- alkenyl, C3-C6-alkynyl, C3-C7-cycloalkyl, C -C6-cyano- alkyl, benzyl or optionally substituted phenyl;
Ri° is hydrogen, Ci-Cε-alkyl, Cι-C6-haloalkyl, optionally substituted phenyl or optionally substituted benzyl;
RH is Cι-C6-alkyl, C2-C6-alkenyl, C3-Cg-alkynyl, C3-C7- cycloalkyl, Ci-Cβ-haloalkyl, optionally substituted phenyl, benzyl or S(0)n-Ri4;
n is an integer of 0 , 1 or 2 ;
A, Ai and A2 are each independently oxygen or sulfur;
X is hydrogen, halogen or Cχ-C -alkyl;
Xi is hydrogen, halogen, Cι-C -alkyl, Cχ-C4-haloalkyl, Cι-C4-alkoxy or Cι-C-haloalkoxy;
V is hydroxyl, halogen, Cι-C4-alkoxy or Cχ-C4-alkylthio;
R88 is cyano, Cι-C-alkyl, Cι-C -haloalkyl, Cχ-C4-alkoxy, Cχ-C -haloalkoxy, Cχ-C4-alkylthio, Cι-C -alkyl- sulfinyl, Cχ-C -alkylsulfonyl or Cι-C4-haloalkyl- sulfonyl;
R89 is hydrogen, cyano, halogen, Cι-C4-alkyl or Cι-C4-halo- alkyl,
Y is an optionally substituted ring of three to seven atoms consisting of carbon and one to four heteroatoms selected from oxygen, sulfur and nitrogen;
Z is oxygen or S(0)m;
m is an integer of 0,1 or 2; and all optical isomers and diastereomers thereof .
2 . The compound according to claim 1 wherein Q is Q7 or Q2 .
R is Ci-Cε-alkyl , C2-Cg-alkenyl , C3-C6-alkynyl or amino; R2 is Cι-C6-alkyl or Ci-Cδ-haloalkyl; R3 is hydrogen; Y is selected from
Figure imgf000290_0001
Yi Y2 Ys
Figure imgf000290_0002
Y7 γ8 Yg
Figure imgf000290_0003
Yl3 Yl4 Yl5
Figure imgf000291_0001
Yl6 Yl7 ■18
Figure imgf000291_0002
Y31 Y32 Y33
Figure imgf000292_0001
Y37 Y38 Y39
Rl5 , Ri 8 , R20 and R2 are each independently hydrogen , Cι~C8- alkyl , Cι-C8-haloalkyl , Cι-C8-alkoxy, Ci-Cg-thioalkyl , halogen , nitro , cyano , hydroxy, C2-C6-alkenyl , C3-Cg- alkynyl , C2-C6-haloalkenyl , C3-C8-cycloalkyl or
R20 and the carbon on Y to which R20 is attached may form an exocyclic double bond or when R20 and R21 are attached to the same carbon of Y25 , R20 ,
R2l and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring ;
Ri6 is hydrogen, halogen, Cι-C8-alkyl optionally substituted with C(0)R22, CO-OR23, X2R24, S(0)m-alkyl, NR86R87, Cι-C8-haloalkyl, C(0)R25, CO-OR26, X3R2?, CH=CHR28, C3-C8-cycloalkyl, N(R29)S02R30 or optionally substituted phenyl, or when Ri5 and RX6 are attached to adjacent carbon atoms, they may be taken together with the atoms to which they are attached to form a six-membered heterocyclic or carbocyclic ring;
Rl? is hydrogen, Cι-C8-alkyl, C2-C8-alkenyl, C3-C6-alkynyl, C(0)R25 or optionally substituted benzyl;
Rl9, R29, R33, R34f R35f R37, R38f R39 , R42 f R43 f R44, R46, R47, R4S, R50, R51f R527 R53 f R55 , R56, R57 f R60, R61f R62,
R64, R65, R66, R69f R70, R71, R73, R74, R75, R76f R80,
R85 and R86 are each independently hydrogen, hydroxy, Cι-C8-alkyl, Cι-C -alkoxy, C3-C8-cycloalkyl, C2-C8-al- kenyl, C3-C6-alkynyl, optionally substituted phenyl or optionally substituted benzyl; R23, R26 R3if R40f R49f R58f R67 and R79 are each independently hydrogen, Cι-C8-alkyl, Cj-Cs-haloalkyl, C3-C8-cyclo- alkyl, C3-Ce-halocycloalkyl, C2-C8-alkenyl, C2-C8- haloalkenyl, C5-C8-cycloalkenyl, C5-C8-halocycloal- kenyl, C3-C8-alkynyl, C3-C8-haloalkynyl, optionally substituted phenyl, optionally substituted benzyl, furfuryl, pyridyl, thienyl, an alkali metal, alkaline earth metal, manganese, copper, zinc, cobalt, silver, nickel, ammonium or organic ammonium cation;
R24, R27 and R28 are each independently hydrogen,
Cι-Cιo-alkyl optionally substituted with one to six halogens, one Cι-C6-alkoxy group, CO-OR31, C(0)R32, C(OR33)2, C(SR34)2, C(0)NR35R36, C(0)ON=CR37R38, cyano, optionally substituted phenyl or C(0)NH-OR39;
C2-Cιo-alkenyl optionally substituted with one Ci-Cβ- alkyl group, one to three halogens, one Ci-Cβ-alkoxy group, CO-OR40, C(0)Rl,C(OR42)2, C(SR43)2, C(0)NR R45, C(0)ON=CR6R47, cyano, optionally substi- tuted phenyl or C(0)NH-OR48;
C3-C8-cycloalkyl optionally substituted with one Ci-Cg-alkyl group, one to three halogens, one Ci-Cβ- alkoxy group, CO-OR49, C(O)R50,C(OR5l)2, C(SR52)2, C(0)NR53R54, C(0)ON=CR55R56, cyano, optionally sub- stituted phenyl or C(0)NH-OR57;
C5-C8-cycloalkenyl optionally substituted with one Ci-Cβ-alkyl group, one to three halogens, Cι-C4-alk- oxy group, CO-OR^8, C(0)R59,C(OR6°)2, C(SR6l)2, C(0)NR62R63f c(0)ON=CR64R65, cyano, optionallysubsti- tuted phenyl or C(0)NH-OR66;
C3-C8-alkynyl optionally substituted with one C -C6- alkoxy group, CO-OR67, C(0)R68,C(OR69)2, C(SR70)2, C(0)NR71R72, C(0)ON=CR73R74, cyano, optionally substituted phenyl or C(0)NH-OR75; phenyl optionally substituted with one to three halogens, one to three Ci-Cβ-alkyl groups, one to three Ci-Cg-alkoxy groups, one to three Cι-C6-halo- alkyl groups, one to three Ci-Cβ-haloalkoxy groups, one cyano, one nitro, one NR76R77, one C(0)R78 or one CO-OR79;
R30 is hydroxy, Cι-C8-alkyl, C3-C8-cycloalkyl, Cχ-C8-halo- alkyl, C2-C8-alkenyl, C2-C8-haloalkenyl, C3-C8-alky- nyl, optionally substituted phenyl, optionally sub- stituted benzyl or NR80R8i; B and Bi are each independently oxygen, sulfur or NRi7;
X2 and X3 are each independently oxygen or sulfur;
and all optical isomers and diastereomers thereof.
3. The compound according to claim 1 wherein wherein Q is Q24; R is Cι-C3-alkyl; R2 is Cι-C3-haloalkyl; X is hydrogen or halogen; Xi is hydrogen; Z is sulfur;
Y is Ylf Y2, Y3, Y , Y5, Ye. io, ii, i4. is, Yie. 22, Y24. 25 Y26. 27/ 28 38 or Y39;
R15, Ri8, R20 and R2l are each independently of one another hydrogen, Cι-C3-alkyl, Cι-C3-haloalkyl, Cι-C3-alkoxy, halogen, hydroxy or when R20 and R2i are attached to the same carbon of Y2s, an epoxide ring is formed;
Ri6 is hydrogen, halogen, Cι-C3-alkyl optionally substituted with C(0)R22, CO-OR23, X2R24 or S(0)m-alkyl; phenyl, Cι-C3-haloalkyl, C(0)R25, CO-OR26, X3R27, C3-C8- cycloalkyl, N(R29)S02-R30 or C2-C4-alkenyl;
Ri7 is hydrogen, Cχ-C3-alkyl, C2-C -alkenyl or C(0)R25;
Ri9, R29 and R80 are each independently hydrogen or Cι-C3- alkyl;
R2 , R25 ancj R8i are each independently hydrogen, Cι-C3-alkyl, optionally substituted phenyl or benzyl;
R23, R26 and R3i are each independently hydrogen, Cι-C3-alkyl, C2-C -alkenyl or C3-C6-alkynyl;
R24 and R27 are each independently hydrogen or Cι-C3-alkyl optionally substituted with one CO-OR3! group or one Cχ-C -alkoxy group;
R30 is Cι-C3-alkyl, C3-C5-cycloalkyl, Cι-C3-haloalkyl, C2-C4- alkenyl, optionally substituted phenyl, optionally substituted benzyl or NR80R8l;
X2 and X3 are oxygen,
. The compound according to claim 1 wherein wherein
Q is
Figure imgf000295_0001
Figure imgf000295_0002
7
Figure imgf000295_0003
Figure imgf000296_0001
Figure imgf000297_0001
Rl5, Rl8 , R20 and R2i are each independently of one another hydrogen, Cι-C3-alkyl, Cι-C3-haloalkyl or Cι-C3-alkoxy;
R16 is hydrogen, halogen, Cι-C8-alkyl optionally substituted with X R24; Cι-C3-haloalkyl, C2-C alkenyl or phenyl;
Ri7 is hydrogen, methyl or C(0)R25;
i is hydrogen or C!-C3-alkyl ;
R24 is hydrogen or Cι-C3-alkyl;
R25 is Cι-C3-alkyl or phenyl;
X2 is oxygen.
The compound according to claim 1 selected from the group consisting of l-methyl-3-[ 3- ( 3-thienyl ) -1, 2-benzisothiazol~5-yl] -6-(trifluoromethyl)uracil; ethyl (R) -2-[ 5-[3 , 6-dihydro-3-methyl-2 ,6-dioxo-4-(trifluoromethyl) -1 ( 2H) -pyrimidinyl] -1, 2-benzisothiazol-3-yl]-4-thiazolidinecarboxylate; l-methyl-3-[ 3- (2-thienyl) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[3-( 3-methyl-2-thienyl) -1,2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[ 3- ( l-methylimidazol-2-yl) -1 , 2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[ 3- ( l-methylpyrrol-2-yl) -1, 2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[3-(4-methyl-2-thiazolyl) -1,2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil; 3-[3-(2 ,5-diethyl-3-thienyl)-1 ,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-pyrodyl ) -1, 2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil;
3-[3-(3-methoxy-2-thienyl)-l,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 3-pyridyl) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl )uracil; l-methyl-3-[3-(2-pyrimidinyl) -1,2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil; 3-[3-[ ( IR,2S)-1,2-epoxypropyl]-1,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[3-[ (1R,2R)-1, 2-epoxypropyl ]-l,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 2-pyridyl) -1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil N' ' ,S,S-trioxide; l-methyl-3-[ 3-( 5-methyl-l, 3 , 4-oxadiazol-2-yl) -1 , 2-benziso- thiazol-5-yl]-6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 5-methyl-l, 3 , 4-thiadiazol-2-yl) -1, 2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil;
1, 2-benzisothiazole-3-carboxanilide, 4 ' -chloro-5-[ 3 , 6-di- hydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl) - 1(2H) -pyrimidinyl]-N-methyl-; l-methyl-3-[ 3-( 3-methyl-2-pyridyl) -1, 2-benzisothiazol- 5-yl]-6-(trifluoromethyl)uracil;
N-[ 3-( 5-methyl-2-thienyl) -1 , 2-benzisothiazol-5-yl] -1-cyclo- hexene-1,2-dicarboximide; l-methyl-3-[3-(5-methyl-2-thienyl) -1,2-benzisothiazol-5-yl]- 6-(trifluoromethyl)uracil;
Methyl [ ( 2-[ 5-[ 3, 6-dihydro-3-methyl-2, 6-dioxo-4-(trifluoromethyl) -1 ( 2H) -pyrimidinyl] -1, 2-benzisothiazol-3-yl] - 3-thienyl]oxy]acetate; methyl 2-[ ( 2-[ 5-[ 3, 6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl) -1 (2H) -pyrimidinyl] -1 , 2-benzisothiazol-3-yl]- 3-thienyl]oxy]propionate;
3-[3-( 1, 3-dithiolan-2-yl) -1 ,2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil; 3- [ 6-fluoro-3-(2-pyridyl) -1, 2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil; l-methyl-3-[ 3- ( 4-methyl-3-thienyl) -1 , 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; 3-[3-( 3 , 5-dimethyl-2-thienyl) -1,2-benzisothiazol-5-yl]- l-methyl-6- (trifluoromethyl)uracil;
3- (3-m-dioxan-2-yl-l, 2-benzisothiazol-5-yl) -l-methyl-6-(trifluoromethyl )uracil;
3-acetyl-2-[5-[3, 6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl) -1 ( 2H) -pyrimidinyl] -1, 2-benzisothiazol-3-yl]thiazoli- dine;
3-benzoyl-2-[ 5-[ 3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-( rifluoromethyl) -1 ( 2H) -pyrimidinyl] -1, 2-benzisothiazol-3-yl]thiazolidine; l-methyl-3-[ 3-( 1, 3-oxathiolan-2-yl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 1, 3-oxathioln-2-yl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil S' ,S'-dioxide; 1,2-benzisothiazole-3-carboxaldehyde, 5-[3 , 6-di- hydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl) -1 ( 2H) - pyrimidinyl]-, 3-[bis (2-hydroxyethyl) dithioacetal] ; l-methyl-3-[ 3-( 1, 3-oxathian-2-yl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 1, 3-oxathian-2-yl) -1 ,2-benzisothiazol-5-yl] -
6-(trifluoromethyl)uracil S' , S '-dioxide;
3-[3 ( 5 , 5-dimethyl-m-dioxan-2-yl) -1, 2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-(4-methyl-m-dioxan-2-yl) -1 ,2-benzisothiazol-
5-yl] -6-(trifluoromethyl )uracil; l-methyl-3-[3-(3-methylpyrazol-l-yl)-1,2-benzisothiazol-
5-yl] -6-(trifluoromethl )uracil;
2-propynyl [ [2-[5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(tri- fluoromethyl) -1 ( 2H) -pyrimidinyl] -1,2-benzisothiazol-3-yl] -
3-thienyl]oxy]acetate;
3-[3-(4, 6-dimethyl-2-pyrimidinyl) -1,2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil;
3-[3-(3-methoxy-2-pyridyl)-l,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-( 5-methyl-2-pyridyl )-1, 2-benzisothiazol-5-yl] -
6-(trifluoromethyl )uracil;
3-[ 3-(4 , 6-diethoxy-2-pyrimidinyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[ 6-fluoro-3-( 3-methyl-2-pyridyl) -1,2-benziso- thiazol-5-yl]-l-methyl-6-(trifluoromethyl)uracil;
3-[3-( 1, 3-dioxolan-2-yl ) -1,2-benzisothiazol-5-yl] -1-methyl-
6-(trifluoromethyl )uracil;
N-[ 6-fluoro-3-( 3-methyl-2-pyridyl ) -1, 2-benzisothiazol-5-yl] - l-cyclohexene-l,2-dicarboximide;
3-[3-[ (4R, 5S) -4 , 5-dimethyl-l ,3-dioxolan-2-yl] -1,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil
3-[3-[ (4R, 5R)-4, 5-dimethyl-l, 3-dioxolan-2-yl]-1, 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-6- (trifluoromethyl) -3-[ 3-( 3 , 4 , 5-trimethylpyrazol-l-yl)-l, 2-benzisothiazol-5-yl]uracil;
3-[ 3-[ ( 4R, 6S ) -4 , 6-dimethyl-m-dioxan-2-yl] -1 ,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil
3-[3-[ (4R, 6S)-4, 6-dimethyl-m-dioxan-2-yl]-l,2-benziso- thiazol-5-yl]-l-methyl-6-(trifluoromethyl)uracil;
3-[3- ( 3-chloro-2-thienyl) -1, 2-benzisothiazol-5-yl] -1-methyl-
6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-thiazolyl) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-methyl-l,3-dioxolan-2-yl) -1,2-benziso- thiazol-5-yl]-6-(trifluoromethyl)uracil; l-methyl-6-(trifluoromethyl) -3-[3-(4 ,4 , 6-trimethyl-m-dio- xan-2-yl)-l,2-benzisothiazol-5-yl]uracil; l-methyl-3-[ 3-(4,4,5 , 5-tetramethyl-l, 3-dioxolan-2-yl ) -
1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 4-methyl-l , 3-dioxolan-2-yl) -1, 2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil;
2 , 4 ( IH, 3H) -pyrimidinedione, l-methyl-3-[3-( 5-methylene- m-dioxan-2-yl) -1,2-benzisothiazol-5-yl] -6-(trifluoromethyl ) -; l-methyl-3-[ 3-( 4-methylpyrazol-l-yl) -1 , 2-benziso- thiazol-5-yl]-6-(trifluoromethyl)uracil;
3-[3-(2-furyl)-1,2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[3-(l,3-dioxolan-2-yl)-6-fluoro-l,2-benziso- thiazol-5-yl ] -l-methyl-6- (trifluoromethyl)uracil; 3-( 3-m-dioxan-2-yl-6-fluoro-1 , 2-benziso- thiazol-5-yl) -l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-[ ( 4R,r% ) -4, 5-dimethyl-l, 3-dioxolan-2-yl] -6-fluoro-1,2-be nzisothiazol-5-yl]-l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-[ 4-(methoxymethyl) -1 , 3-dioxolan-2-yl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[3-(3 ,6-dihydro-4 , 6 , 6-trimethyl-2H-pyran-2-yl) -1,2-benziso- thiazol-5-yl]-l-methyl-6-(trifluoromethyl)uracil;
3-[3-[ (4R,5S-)-4 ,5-dimethyl-l,3-dioxolan-2-yl]-6-fluoro-1,2-b enzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[3-[ ( 4R,6S) -4, 6-dimethyl-m-dioxan-2-yl] -6-fluoro-1 ,2-benz- isothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
2 , 4 ( IH, 3H) -pyrimidinedione, l-methyl-3-[3-(2-methyl-3-thienyl)-1,2-benziso- thiazol-5-yl] -6-(trifluoromethyl ) -; 3-[3-[5-(bromomethyl)-5-hydroxy-m-diaxan-2-yl]-l,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-( 3-spiro[m-dioxane-5, 2 '-oxiran] -2-yl-1 , 2-benziso- thiazol-5-yl) -6-(trifluoromethyl)uracil;
3-[3-( 4 , 4-dimethyl-5-oxo-1 , 3-dioxolan-2-yl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-[ 4-(chloromethyl ) -1, 3-dioxolan-2-ylJ -1 , 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil;
3-[3-[4-(hydroxymethyl )-1 , 3-dioxolan-2-yl]-1 , 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[3-( 4-isopropyl-2-oxazolin-2-yl) -1,2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl)uracil; l-methyl-3-[3 (2-oxazolin-2-yl) -1,2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-6-(trifluoro- methyl) -3-[3- (4-vinyl-l,3-dioxolan-2-yl)-1,2-benziso- thiazol-5-yl ]uracil; l-methyl-3-[ 3-( 4-propyl-l, 3-dioxolan-2-yl) -1,2-benziso- thiazol-5-yl] -6- (tri luoromethyl)uracil; l-methyl-3-[ 3-( 4-phenyl-l, 3-dioxolan-2-yl) -1, 2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil; 3-[3-[ 4-(bromethyl) -1, 3-dioxolan-2-yl] -1,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[3-[3-(bromomethl) -2-thienyl]-1,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[ 3-[ 3-(methoxymethyl) -2-thienyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[ 3- ( 3 , 4-dimethyl-2-thienyl) -1, 2-benziso- thiazol-5-yl]-l-methyl-6-(trifluoromethyl)uracil; 3-[ 3- ( 3-f ryl) -1 , 2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-[4-[ (methylthio)methyl]-1,3-dioxolan-2-yl]- 1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; 3-[ 3-[ 3-(hydroxymethyl) -2-thienyl] -1, 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[ 3-[ 4-[ (methylsulfonyl)methyl]-1, 3-dioxolan-2-yl] - 1 ,2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[3-[4-f (methylsulfonyl)methyl]-l,3-dioxolan-2-yl]- 1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[3-[4-[ (methylsulfinl)methyl ]-1 , 3-dioxolan-2-yl ]- 1,2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; [2-[ 5-[ 3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl)-1 (2H) -pyrimidinyl]-1,2-benziso- thiazol-3-l]-l, 3-dioxolan-4-yl]methyl thiocyanate; 3-[ 3- ( 3 , 4-dihydro-3-oxo-2-quinoxalinyl) -1, 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 5-[ 5-[ 3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl) -
1 ( 2H) -pyrimidinyl ] -1 , 2-benzisothiazol-3-yl] -1, 6-hydro-6-oxo- 2 , 3-pyrazinedicarbonitrile; l-methyl-3-[ 3- ( 4-oxo-delta-2-l , 2 , 5-thiadiazolin-3-yl) -1, 2- benzisothiazol-5-yl] -6-(trifluoromethyl)uracil S ' ,S '-dioxide; 3-[3-[2-(dimethylamino)-4-methoxy-5-oxo-2-imidazolin-4-yl]- 1, 2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3- [3-( 4-hydroxy-5-oxo-2-phenyl-2-imidazolin-4-yl) -1,2-benz- isothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[3-(2-tert-butyl-4-hydroxy-5-oxo-2-imidazolin-4-yl)- l,2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl) racil; 3-[3-( -hydroxy-5-imino-4 , 4-dimethyl-2-oxo-3-pyrrolidinyl) -1 , 2 -benzisothiazol-5-yl ]-l-methyl-6-(trifluoromethyl)uracil; 3-[ 3 [ 4-methoxy-2-(methylimino) -5-oxo-4-imidazolidinyl] -1, 2- benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil and 3-[3 [4-methoxy-2-(ethylimino) -5-oxo-4-imidazolidinyl] -
1,2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil.
6. A method of controlling undesirable vegetation, which comprises allowing a herbicidally active amount of at least one compound of the formula I as defined in claim 1, to act on plants, their environment or on seed.
5
7. The method according to claim 6 wherein the compound is applied to the foliage of the undesirable plant species or to the soil or water containing seeds or other propagating organs thereof in the presence of crop plants, crop seeds or
10 other crop propagating organs.
8. The method according to claim 6 wherein the crop is a cereal crop.
15 9. The method according to claim 6 wherein the cereal crop is selected from the group consisting of corn, wheat and rice.
10. The method according to claim 6 wherein the cereal crop is corn and the compound is selected from the group consisting
20 of l-methyl-3-[3-(3-thienyl)-l,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil;
3-[3-( 3-chloro-2-thienyl)-1,2-benzisothiazol-5-yl]-1-methyl- 6-(trifluoromethyl)uracil;
25 3-[ 3-( 3 , 4-dimethyl-2-thienyl) -1, 2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil;
3-[ 3-[ ( 4R, 5S ) -4 , 5-dimethyl-l, 3-dioxolan-2-yl] -1 , 2-benziso- thiazol-5-yl ] -l-methyl-6-(trifluoromethyl)uracil; 3-[3-[ (4R,5R) -4 , 5-dimethyl-l, 3-dioxolan-2-yl] -1 ,2-benziso-
30 thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil and ethyl (R) -2- [ 5-[ 3 , 6-dihydro-3-methyl-2 , 6-dioxo-4-(trifluoromethyl ) -1 (2H) -pyrimidinyl] -1,2-benzisothiazol-3-yl]-4-thiazolidinecarboxylate .
35 11. The method according to claim 6 wherein the cereal crop is wheat and the compound is selected from the group consisting of l-methyl-3- [ 3-( 3-thienyl) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl )uracil;
40 l-methyl-3-[ 3- ( 2-thienyl ) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; l-methyl-3-[3-(3-methyl-2-thienyl)-1 ,2-benzisothiazol-5-yl]- 6-(trifluoromethyl)uracil; l-methyl-3-[3-(5-methyl-2-thienyl)-l,2-benzisothiazol-5-yl]-
45 6-(trifluoromethyl)uracil;
3-[ 3-( 3-chloro-2-thienyl) -1, 2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil; 3-[3-(3 , 4-dimethyl-2-thienyl ) -1 , 2-benzisothiazol-5-yl ] - l-methyl-6-(trifluoromethyl )uracil;
3- [ 3-(2 , 5-diethyl-3-thienyl) -1 , 2-benzisothiazol-5-yl] - l-methyl-6- (trifluoromethyl )uracil; 3- [ 3- ( 3-methoxy-2-pyridyl ) -1, 2-benzisothiazol-5-yl ] -1-methyl- 6- (trifluoromethyl)uracil;
3- [3- [(4R,5S) -4, 5-dimethyl-l, 3-dioxolan-2-yl ]-l, 2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl)uracil; 3- [ 3- [ ( 4R, r% ) -4 , 5-dimethyl-l , 3-dioxolan-2-yl] -6-fluoro- 1,2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; 3-[ 3-[ 4- ( hydroxymethyl ) -1 , 3-dioxolan-2-yl ] -1 , 2-benziso- thiazol-5-yl ] -l-methyl-6- (trifluoromethyl )uracil; l-methyl-6- (trifluoromethyl ) -3-[ 3- ( 4-vinyl-l, 3-dioxolan- 2-yl)-l,2-benzisothiazol-5-yl]uracil; l-methyl-3- [ 3- ( 4-propyl-l , 3-dioxolan-2-yl ) -1 , 2-benziso- thiazol-5-yl ] -6- (trifluoromethyl )uracil ; 3-[ 3-[ 4-(bromethyl) -1 , 3-dioxolan-2-yl ] -1 ,2-benziso- thiazol-5-yl] -l-methyl-6- (trifluoromethyl)uracil; 3-[ 3- (4-isopropyl-2-oxazolin-2-yl ) -1 , 2-benzisothiazol-5-yl ] - l-methyl-6- (trifluoromethyl)uracil and ethyl (R) -2- [ 5-[ 3 , 6-dihydro-3-methyl-2 , 6-dioxo-4- (trifluoromethyl ) -1 ( 2H) -pyrimidinyl ] -1 , 2-benzisothiazol-3-yl ] -4-thiazolidinecarboxylate .
The method according to claim 6 wherein the cereal crop is rice and the compound is selected from the group consisting of l-methyl-3- [ 3- ( 5-methyl-2-thienyl ) -1 , 2-benzisothiazol-5-yl ] -
6- trifluoromethyl )uracil ; 3- 3- ( 3-chloro-2-thienyl ) -1 , 2-benzisothiazol-5-yl ] -1-methyl- 6- trifluoromethyl)uracil ; 3- 3- [ 3- (methoxymethyl ) -2-thienyl] -1 , 2-benzisothiazol-5-yl ] - l-methyl-6- (trifluoromethyl)uracil;
3- [ 3-( 3 , 4-dimethyl-2-thienyl) -1 , 2-benzisothiazol-5-yl] - l-methyl-6- ( trifluoromethyl )uracil;
3- [ 3- ( 2 , 5-diethyl-3-thienyl ) -1 , 2-benzisothiazol-5-yl ] - l-methyl-6- ( trifluoromethyl )uracil;
3- 6-fluoro-3-( 2-pyridyl) -1 , 2-benzisothiazol-5-yl] -1-methyl- 6- trifluoromethyl )uracil; 3- 3- ( 3-methoxy-2-pyridyl) -1, 2-benzisothiazol-5-yl] -1-methyl- 6- trifluoromethyl ) racil; l-methyl-3- [ 3- ( 5-methyl-2-pyridyl ) -1 , 2-benzisothiazol-5-yl ] -
6- (trifluoromethyl )uracil ;
3-[ 6-fluoro-3- ( 3-methyl-2-pyridyl ) -1 , 2-benzisothiazol-5-yl ] - l-methyl-6-(trifluoromethyl)uracil;
3- [ 3- ( 1 , 3-dioxolan-2-yl ) -1 , 2-benzisothiazol-5-yl ] -1-methyl-
6-(trifluoromethyl)uracil; 3-[3-[ (4R,5S) -4 ,5-dimethyl-l,3-dioxolan-2-yl]-1,2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[3-(2-methyl-l,3-dioxolan-2-yl)-1,2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil; 3-[ 3-[ ( 4R,r% ) -4 , 5-dimethyl-l, 3-dioxolan-2-yl]-6-fluoro- l,2-benzisothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-6-(trifluoromethyl) -3-[ 3-( -vinyl-l, 3-dioxolan- 2-yl)-l,2-benzisothiazol-5-yl]uracil; l-methyl-3-[3-(4-propyl-l, 3-dioxolan-2-yl)-l,2-benziso- thiazol-5-yl] -6-(trifluoromethyl)uracil;
3-[ 3-( 4-isopropyl-2-oxazolin-2-yl ) -1,2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[ 3-(2-thiazolyl) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil and ethyl (R)-2-[5-[3, 6-dihydro-3-methyl-2, 6-dioxo-4-(trifluoromethyl) -1 (2H) -pyrimidinyl]-1, 2-benzisothiazol-3-yl]-4-thiazolidinecarboxylate.
13. The method according to claim 6 wherein the crop is soybean.
14. The method according to claim 13 wherein the compound is selected from the group consisting of l-methyl-3-[ 3-( 3-thienyl) -1, 2-benzisothiazol-5-yl] -6-(trifluoromethyl)uracil; 3-[ 3-( 3-Methoxy-2-thienyl) -1, 2-benzisothiazol-5-yl] -1-methyl-
6-(trifluoromethyl)uracil; l-methyl-3-[ 3-( 5-methyl-2-thienyl) -1, 2-benzisothiazol-5-yl] -
6-(trifluoromethyl)uracil;
3-[ 3-( 3-chloro-2-thienyl ) -1, 2-benzisothiazol-5-yl] -1-methyl- 6-(trifluoromethyl)uracil;
3-[3-(3, 4-dimethyl-2-thienyl) -1 ,2-benzisothiazol-5-yl]- l-methyl-6-(trifluoromethyl)uracil;
3-[3-(3-methoxy-2-pyridyl)-1, 2-benzisothiazol-5-yl] -1-methyl-
6-(trifluoromethyl )uracil; l-methyl-3-[ 3-( 5-methyl-2-pyridyl ) -1, 2-benzisothiazol-5-yl] -
6-(trifluoromethyl)uracil;
3-[ 3-[ 4-(hydroxymethyl) -1 , 3-dioxolan-2-yl] -1 , 2-benziso- thiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil; l-methyl-3-[ 3-(2-pyrimidinyl) -1, 2-benzisothiazol-5-yl] - 6-(trifluoromethyl)uracil;
3-[ 3-[ ( 4R, 6S ) -4 , 6-dimethyl-m-dioxan-2-yl] -6-fluoro-1 , 2-benz- isothiazol-5-yl] -l-methyl-6-(trifluoromethyl)uracil and
3-[3-(4-isopropyl-2-oxazolin-2-yl) -1, 2-benzisothiazol-5-yl] - l-methyl-6-(trifluoromethyl)uracil.
15. The method according to claim 6 wherein the compound is applied to the foliage of the undesirable plant species or to the soil or water containing seeds or other propagating organs thereof at a rate of about 0.001 kg/ha to 1 kg/ha.
16. A herbicidal composition which comprises at least one inert solid and/or liquid carrier and a herbicidally effective amount of at least one compound of the formula I as defined in claim 1.
17. An compound of formula II, XLIV or XL
Figure imgf000306_0001
wherein X is hydrogen, halogen or Cι-C4-alkyl; Xi is hydrogen, halogen, Cι-C -alkyl, Cι-C-haloalkyl, Cχ-C4-alkoxy or Cι-C -haloalkoxy;
Y is an optionally substituted three to seven-membered heterocyclic ring containing one to four heteroatoms selected from oxygen, sulfur and nitrogen;
Z is 0 or S(0)m; m is zero, 1 or 2;
R2 and R3 are, independently of one another, hydrogen, halogen, Ci-Cβ-alkyl, Cι-C6-haloalkyl, C3-C7~cyclo- alkyl, C2-C6-alkenyl, C2-Cg-haloalkenyl, C3-C6-al- kynyl, OR8, S(0)m-R9, NR1°RH or
R2 and R3, together with the atoms to which they are attached, form a four to seven-membered saturated or unsaturated ring optionally interupted by oxygen, sulfur or nitrogen and optionally substituted with one to three methyl groups or one or more halogen atoms; and all optical isomers and diastereomers thereof.
18. A compound according to claim 17 wherein Y is selected from
Figure imgf000306_0002
Yi 2 3
Figure imgf000307_0001
Yl3 Yl4 Yl5
Figure imgf000307_0002
Yl6 Yl7 Yi8
Figure imgf000307_0003
Figure imgf000308_0001
Y31 Y32 Y33
Figure imgf000308_0002
Y34 Y35 Y36
Figure imgf000308_0003
Y40 wherein
Ri5, RX8, R20 and R21 are, independently of one another, hydrogen, Cχ-C8-alkyl, Cι-C8-haloalkyl, Cι-C8-alkoxy,
Cι-C8-thioalkyl, halogen, nitro, cyano, hydroxy,
C2-C6-alkenyl, C3-C6-alkynyl, C2-Cg-haloalkenyl,
C3-C8-cycloalkyl or R20 and the carbon on Y to which
R20 is attached may form an exocyclic double bond or when R2o and R2χ are attached to the same carbon of γ25r 20/ R 2i and the carbon to which they are bonded may form a three- to six-membered heterocyclic ring;
R16 is hydrogen, halogen, Cι-C8 alkyl optionally substituted with C(0)R22, CO-OR23, X2R24, S(0)malkyl, NR86R87, Cι-C8 haloalkyl, C(0)R25, C02R26, X3 R 27. CH=CHR28, C3-C8 cycloalkyl, N(R2g)S02R3o or optionally substituted phenyl, or when Ri5 and Ri6 are attached to separate adjacent carbons, as in Y2 , they may form a six-membered heterocyclic or carbocyclic ring fused to the Y-ring;
R17 is hydrogen, Cχ-C8 alkyl, C2-C8 alkenyl, C3-C6 alkynyl, C(0)R25, or ( subst. )benzyl;
R19' R29f R33 R34r 35r R37 R38 &39 r R42f R43r R44/ R46Λ 47f 48/ 50/ R51f R52f R53 r 55f R56f R571 R60f 61r R621 R64f 65f R66 R69 70c R71/ R73 r R74 75f 76/ R80 and R85 are each independently hydrogen, OH, Cι-C8 alkyl, Cι-C alkoxy, C3-C8 cycloalkyl, C2-C8 alkenyl,
C3-C6 alkynyl, (subst.) benzyl or (subst.) phenyl; R23/ 26 R3i. 40/ R49f R58f R67 and R79 are each independently hydrogen, Cι-C8 alkyl, Cι-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C2-C8 alkenyl, C -C8 haloalkenyl, Cs-C8 cycloalkenyl, Cs-C8 halocycloalke- nyl, C3-C8 alkynyl, C3-C8 haloalkynyl, (subst. )benzyl, (subst.) phenyl, furfuryl, pyridyl, thienyl, an alkali metal, alkaline earth metal, manganese, copper, zinc, cobalt, silver, nickel ammonium or organic ammonium cation;
R 24/ 27f nd R 28 are each independently hydrogen,
C1-C10 alkyl optionally substituted with one to six halogens, one Cι-C6 alkoxy group, C02R3χ, C(0)R32,
C(OR33)2, C(SR3 )2, C(0)NR35R36, C(0)ON=CR37R38, cyano, (subst. )phenyl or C(0)NHOR39; C2-Cιo alkenyl optionally substituted with one Ci-Cβ alkyl group, one to three halogens, one Ci-Cβ alkoxy group, CO2R40, C(0)R4ι,C(OR42)2, C(SR43)2, C(0)NR44R5,
C(0)ON=CR6R4 , cyano, (subst. )phenyl or C(0)NHOR48; C3-C8 cycloalkyl optionally substituted with one C1-C6 alkyl group, one to three halogens, one Cχ-C6 alkoxy group, C02R49, C(O)R50,C(OR51)2, C(SR52)2. C(0)NR53R54, C(0)ON=CR55R56, cyano, (subst. )phenyl or C(0)NH0R57; C5-C8 cycloalkenyl optionally substituted with one Ci-Cε alkyl group, one to three halogens, C1-C4 alkoxy group, C02R58, C(0)R59,C(OR6o)2, C(SR6ι)2, C(0)NR62R63, cyano, (subst. )phenyl or C(0)NHOR66 ; C3-C8 alkynyl optionally substituted with one Ci-Cε alkoxy group, C02R67, C(0)R68,C(OR69)2, C(SR70)2, C(0)NR71R72, C(0)ON=CR73R74, cyano, (subst .)phenyl or C(0)NHOR75;
phenyl optionally substituted with one to three halogens, one to three Cι-C6 alkyl groups, one to three Ci-Cε alkoxy groups, one to three Ci-Cβ haloalkyl groups, one to three Cι-C6 halo- alkoxy groups, one cyano, one nitro, one NR76R77, one C(0)R8 or one C02R79;
R30 is OH, Cι-C8 alkyl, C3-C8 cycloalkyl, Cχ-C8 haloalkyl, C2-C8 alkenyl, C2-C8 haloalkenyl, C3-C8 alkynyl, (subst. )benzyl, (subst.) phenyl, or NR8oR8ι; B and Bi are each independently oxygen, sulfur or NRχ7; X2 and X3 are each independently 0 or S;
and all optical isomers and diastereomers thereof.
19. The compound according to claim 17 wherein X is hydrogen or halogen; Xi is hydrogen;
Z is sulfur of oxygen;
Y is selected from Yl r Y2, Y3, Y4, Y5, Y6, Y10, Y11, Yi4 Y15, i6, 22, 24. Y25. Y26 Y27, 28, 38, and Y39. Ri5 Ri8f R 20. and R2i are each independently hydrogen, Cι-C3 alkyl, C1-C3 haloalkyl, Cχ-C3 alkoxy, halogen, hydroxy or when R20 and R2χ are attached to the same carbon of Y25 an epoxide ring is formed; i6 is hydrogen, halogen, Cχ-C3 alkyl optionally substituted with C(0)R2 , C02R23, X2R24, or S(0)malkyl; phenyl; Cχ-C3 haloalkyl, C(0)R25, C02R26, X3R27 C3-C8 cycloalkyl, N(R29)SO2R30 or C2-C4 alkenyl; Rl7 is hydrogen, Cχ-C3 alkyl, C2-C alkenyl or C(0)R25; R19, R29 and R80 are each independently hydrogen or C1-C3 alkyl ; R22, R25 and R8χ are each independently hydrogen, C1-C3 alkyl, benzyl or (subst)phenyl; 23r R 26 and R 3i are each independently hydrogen, Cι-C3 alkyl,
C2-C alkenyl, or C3-C6 alkynyl; R4 and R27 are each independently hydrogen or Cι-C3 alkyl op- tionally substituted with one C02R3ι group or one
C1-C3 alkoxy group; R30 C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 haloalkyl, C2-C4 alkenyl (subst. )benzyl, (subst. )phenyl, or NR80R8ι;
X2 and X3 are oxygen.
20. The compound according to claim 17 wherein Y is taken from
Figure imgf000311_0001
Figure imgf000311_0002
Figure imgf000311_0003
RK 1,6
Figure imgf000312_0001
15 - 16
Figure imgf000312_0002
R15/ Ri8/ R20 and R χ are each independently hydrogen, C -C3 alkyl, C1-C3 haloalkyl, Cι-C3 alkoxy; Ri6 is hydrogen, halogen, Cι-C8 alkyl optionally substituted with X2R24; C1-C3 haloalkyl, phenyl or C2-C4 alkenyl; Ri7 is hydrogen, methyl or C(0)R25; R19 is hydrogen or C1-C3 alkyl; R24 is hydrogen or C1-C3 alkyl; R 5 is C1-C3 alkyl or phenyl; X is oxygen .
21. Compound XL according to claim 17 wherein R2 is trif lurormethyl;
Z is sulfur;
Y is taken from
Figure imgf000313_0001
.R 1.6
N-
Y11 ^-^S
Figure imgf000313_0002
Figure imgf000314_0001
Ri5f R18/ R20/ an<3 2i are each independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, Cχ-C3 alkoxy; Ri6 is hydrogen, halogen, Cχ-C8 alkyl optionally substituted with X R24; C1-C3 haloalkyl, phenyl or C2-C4 alkenyl; Rχ7 is hydrogen, methyl or C(0)R2s; R 4 is hydrogen or C1-C3 alkyl; R25 is Cχ-C alkyl or phenyl; R19 is hydrogen or C1-C3 alkyl;
X2 is oxygen.
22. An intermediate compound having the structural formula CXIII
Figure imgf000315_0001
(CXIII) and all optical isomers and diastereomers thereof, wherein Q, X, ι and Z ae as diefined in claim 1 and R85 is Cι-C6-alkyl, C2-C6-alkenyl, C2-Cg-alkynyl, C3-C-cy- cloalkyl or benzyl.
23. The compound according to claim 22 wherein Q is Q7 or Q24
R is Ci-Cβ-alkyl, C2-C6_alkenyl, C3-C6-alkynyl or NH2; R2 is Cχ-C6-alkyl or Ci-Cε-haloalkyl; R3 is hydrogen;
24. The compound according to claim 22 wherein
Q is Q24;
R is C2-C3-alkyl;
R2 is Cι-C3-haloalkyl;
Z is sulfur;
X is hydrogen or halogen;
Xi is hydrogen;
25. The compound according to claim 22 wherein Q is CH,
Figure imgf000315_0002
and Z is sulfur.
26. A process for the preparation of a compound of formula la
Figure imgf000315_0003
wherein R, R2, R3, X, xlf Y and Z are as defined in claim 1, and all optical isomers and diastereomers thereof, which process comprises (a) reacting an amine of formula II
Figure imgf000316_0001
with a 2-dialkylamino-6H-l,3-oxazin-6-one having the structural formula XXXIX
(XXXIX)
Figure imgf000316_0002
4al yl)2
in the presence of an organic acid to form an intermediate compound of formula XL
Figure imgf000316_0003
and (b) reacting the intermediate compound with an electrophile Z^R, wherein Zi is chlorine, bromine or iodine, in the presence of a base.
A process for the preparation of a compound of formula XL
Figure imgf000316_0004
(XL) wherein R2, R3, X, χl Y and Z are as defined in claim 1, and all optical isomers and diastereomers thereof, which process comprises reacting an amine of formula II
Figure imgf000316_0005
with a urea of formula XLI
Figure imgf000317_0001
(XLI), wherein Z is Ci-Cg-alkyl and R82 and R83 are, independently of one another, Ci-Cβ-alkyl or R82 and R83 may be taken together with the atom to which they are attached to form a 5- or 6-membered ring optionally containing one oxygen atom, in the presence of a base.
28. A process for the preparation of a compound of formula la
Figure imgf000317_0002
wherein R2, R3, X, Xi, Y and Z are as defined in claim 1, and all optical isomers and diastereomers thereof, which process comprises reacting an amine of formula II
Figure imgf000317_0003
with a carbamate having the structural formula LXII
Figure imgf000317_0004
(LXII) wherein Z2 is Cι-C6-alkyl and R84 is Cι-C6-alkyl, benzyl, C2-C6-alkenyl, C2-C6-alkynyl or C3-C -cyclopropyl, in the presence of a base.
29. A process for the preparation of a compound of formula II
Figure imgf000318_0001
(II) wherein
X is hydrogen, halogen or Cι-C -alkyl;
Xi is hydrogen, halogen, Cι-C4-alkyl, Cj.-C -haloalkyl, Cι-C4-alkoxy or C!-C4-haloalkoxy; z is 0 or S(0)m; is zero, 1 or 2;
Y is an optionally substituted three to seven-membered heterocyclic containing one to four heteroatoms selected from oxygen, sulfur and nitrogen,
which process comprises reacting an amine of formula XLVII
(XLVII)
Figure imgf000318_0002
with sodium or potassium thiocyanate and bromine to form an isothiocyanate having the structural formula XLVIII
(XLVIII)
Figure imgf000318_0003
and reacting said isothiocyanate with an ammonium salt.
PCT/EP2001/004356 2000-04-17 2001-04-17 Herbicidal 3-heterocyclic substituted benzisothiazole and benzisoxazole compounds WO2001079203A1 (en)

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US8354421B2 (en) 2007-06-29 2013-01-15 Korea Research Insitute Of Chemical Technology HIV reverse transcriptase inhibitors
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