PROCESS FOR THE PREPARATION OF 6-(PERFLUOROALKYL)URACIL COMPOUNDS FROM CARBAMATE COMPOUNDS

Abstract: An improved process for the preparation of 6-(perfluoroalkyl)uracil compounds having structural formula (I) from carbamate compounds having structural formula (II).

Description: PROCESS FOR THE PREPARATION OF 6- (PERFLUOROALKYL) URACIL COMPOUNDS FROM CARBAMATE COMPOUNDS BACKGROUND OF THE INVENTION 6- (Perfluoroalkyl) uracil compounds are useful as herbicidal agents and methods for their preparation are known in the art. 6- (Perfluoroalkyl) uracil compounds may be prepared by reacting 2- (N,N-disubstituted) amino-4- (per- fluoroalkyl) -1, 3-oxazin-6-one compounds with amine compounds . Bull. Soc. Chem. Belg. , 102(4), pages 313-321 (1992) discloses that 2- (N,N-dialkyl) amino-4- (trifluoromet yl) - 1, 3 -oxazin-6 -one compounds are prepared by reacting ethyl 3-amino-4,4,4-trifluorocrotonate with phosgene iminium chloride compounds. However, this method is not entirely satisfactory because the required phosgene iminium chloride compounds are difficult to handle and relatively expensive. Accordingly, a need exists in the art for an improved process for the preparation of 6- (perfluoroalkyl) uracil compounds which avoids the use of 2- (N,N-disubstituted) - amino-4- (perfluoroalkyl) -1, 3 -oxazin-6-one compounds. It is, therefore, an object of the present invention to provide an improved process for the preparation of 6- (perfluoroalkyl) uracil compounds which avoids the use of 2- (N,N-disubstituted) amino-4- (perfluoroalkyl) -1,3 -oxazin- 6 -one compounds . Other objects and advantages of the present invention will be apparent to those skilled in the art from the description below and the appended claims. STMMARY OF THE INVENTION The present invention provides a new process for the preparation of 6- (perfluoroalkyl) uracil compounds having the structural formula I wherein n is an integer of 1, 2, 3, 4, 5 or 6 ; Y is hydrogen or Ci-Cgalkyl; and Q is a Ci-Cgalkyl group or an optionally substituted phenyl, benzyl, heteroaryl or methyleneheteroaryl group, which process comprises : (a) reacting a carbamate compound having the structural formula II (ID wherein Z and Z 1 are each independently or benzyl optionally substituted on the phenyl ring with any combination of from one to three halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl groups; and n and Y are as described above, with an amine compound having the structural formula III QNH 2 (III) wherein Q is as described above, in the presence of a base, to form the 6- (perfluoroalkyl) uracil compound of formula I wherein Y is hydrogen or C j -Cgalkyl; and (b) optionally alkylating the formula I compound wherein Y is hydrogen to form the formula I compound wherein Y is Ci-Cgalkyl. DETAILED DESCRIPTION OF THE INVENTION In a preferred embodiment of the present invention, a carbamate compound of formula II is reacted with an amine compound of formula III and a base, preferably at a temperature ranging from about 20°C to 150°C, in the presence of a solvent . In another preferred embodiment of the present invention, the double bond in the formula II compounds is predominately in the (Z) - configuration. Advantageously, the present invention provides an improved process for the preparation of 6- (perfluoroalkyl) - uracil compounds which avoids the use of 2- (N,N-disub- stituted) amino-4- (perfluoroalkyl) -1, 3-oxazin-6-one compounds . The product formula I compounds may be isolated using conventional isolation procedures such as diluting the reaction mixture with water and separating the product or extracting the product with a suitable extraction solvent. In the isolation procedure, conventional extraction solvents such as diethyl ether, ethyl acetate, toluene, methylene chloride, and the like, and mixtures thereof may be utilized. Bases suitable for use in the process of the present invention include, but are not limited to, tri(C 1 -C 6 . alkyl) amines such as trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine and the like; heterocyclic tertiary amines such as 1,8-diaza- bicyclo [5.4.0] ndec-7-ene (DBU) , 1, 5-diazabicyclo- [4.3.0]non-5-ene (DBN) , 1, 4-diazabicyclo [2.2.2] octane, pyridine, substituted pyridines, quinoline, substituted quinolines and the like; and alkali metal C._-C 6 alkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like. Preferred bases include 1, 8-diazabicyclo- [5.4.0]undec-7-ene and 1, 5-diazabicyclo [4.3.0] non-5-ene . Solvents suitable for use in step (a) of the process of this invention include, but are not limited to, carboxylic acid amides such as N,N-dimethylformamide, N,N- dimethylacetamide and the like; dialkyl sulfoxides such as dimethyl sulfoxide and the like; aromatic hydrocarbons such as toluene, benzene, xylenes, mesitylene and the like; halogenated aromatic hydrocarbons such as chlorobenzene, fluorobenzene and the like; aliphatic hydrocarbons such as pentane, hexane, heptane and the like; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1, 2-dichloroethane and the like; alcohols such as methanol, ethanol, n-propanol , sec-propanol and the like; ketones such as acetone, methyl ethyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane, 1, 2-dimethoxyethane and the like; nitriles such as acetonitrile, propionitrile and the like,- and water; and mixtures thereof. Alkylation procedures suitable for use in this invention include conventional procedures known in the art . In a preferred embodiment of this invention, the step (b) alkylation procedure comprises reacting the formula I compound wherein Y is hydrogen with an alkyl halide having the structural formula IV or a dialkylsulfate ester having the structural formula V 0 XY II or YOSOY ( IV) II O (V) wherein X is chlorine, bromine or iodine, and Y is in the presence of a base. Bases suitable for use in the alkylation procedures of this invention include conventional bases known in the art including, but not limited to, alkali metal hydrides such as sodium hydride and the like; alkali metal C- L -Cgalkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like; alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkaline earth metal hydroxides such as calcium hydroxide and the like; and alkaline earth metal carbonates such as calcium carbonate and the like. Preferred formula II compounds for use in the process of this invention are those wherein Y is hydrogen or C 1 -C 4 alkyl; Z and Z x are each independently C 1 -C 4 alkyl; and n is 1. More preferred carbamate compounds of formula II for use in the process of the present invention are those wherein Y is hydrogen or methyl; Z and Z x are each independently methyl or ethyl; and n is 1. Preferred formula I compounds which may be prepared by the process of the present invention are those wherein n is 1; Y is hydrogen or C 1 -C 4 alkyl; is CH 2 or a bond; - . is CX 5 or N; G 2 is CX 4 or N; X- L is hydrogen, halogen or a C^C g alkyl group optionally substituted with one epoxy group, X 2 is hydrogen, halogen NRR._, C0 2 R 2 , C(0)R 3 , OR 4 , S0 2 R 5 , S0 2 NR 6 R 7 , C(R β ) (OR 9 ) 2 , C (R 10 ) =NOR 11# C (R 12 ) =C (R 13 ) - C ( OR 14 ) =NOR 15 , CH 2 0 - NC0 2 R 16 , 1, 3-dioxolane optionally substituted with one C- L -Cgalkoxy group or one or two C 1 -C 4 alkyl groups , 1, 3-dioxolinone optionally substituted with one Ci-C 8 alkoxy group or one or two C 1 -C 4 alkyl groups, or C 1 -C 4 alkyl optionally substituted with one C0 2 R 2 group and one halogen atom, and X 3 is hydrogen, halogen, C 1 -C 4 haloalkyl, C0 2 R 17 , cyano, C 1 -C 4 haloalkoxy, OR 18 or C 1 -C 4 alkyl, or when X x and X 2 are taken together with the atoms to which they are attached, they may form a five- or six- membered ring wherein X X X 2 or X 2 X X is represented by: -OC(R 20 ) (R 21 )0-, -CH 2 S(0) p N(R 22 )-, -SC(R 23 )=N-, -CH=CH- CH(R 1X )0-, -OC(0)N-, -SC(R 24 )=N-, -ON (R 25 ) C (0) - , -0C(C0 2 R 26 )=C(R 27 )-, -NC(R 28 )=C(SR 29 ) -, -CH=C (CO 2 R 30 ) O- , -CH 2 CH(R 31 )0- or -OC (R 32 ) (R 33 ) C (0) - , or when X 2 and X 3 are taken together with the atoms to which they are attached, they may form a five- or six- membered ring wherein X 2 X 3 or X 3 X 2 is represented by: -NC(R 34 )=NC(S)-, -N(R 35 )N=C(R 36 )-, -N (R 37 ) C (R 38 ) =N- , -N(R 38 )C(0)CH 2 0-, -N(R 39 )C(0)CH=CH-, -S-N=C (R 40 ) - , -0-N=C(R 41 )-, -N=N-N(R 42 ) -, -C (R 43 ) (R 44 ) C (0) N (R 45 ) - or -N(R 4 4 e 6)' ( VR" 4 4 7 7)' X 4 is hydrogen, halogen or OR 19 ; X 5 is hydrogen or halogen; R, R 56 , R 64 , R 69 , R 70 , R 77 and R 91 are each independently hydrogen, S0 2 R 49 , C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, C 3 -Cgalkynyl, phenyl or benzyl; R x is hydrogen, SO 2 R 50 , C(0)R 51 , amino or C 1 -C 4 alkyl optionally substituted with C0 2 R 52 or C(0)R 53 ; R∑ R-16' ^17 ^-26' ^30' ^-68 75' ^76' ^82 an R 88 are each independently hydrogen, C- L -Cghaloalkyl, C 3 -C 8 alkenyl , C 3 -C 6 alkynyl, phenyl, benzyl, f urf uryl , pyridyl , thienyl , C 1 -C 8 alkyl optionally substituted with C0 2 R 54 , morpholine or C(0)R 55 , or an alkali metal, an alkaline earth metal, ammonium or organic ammonium cation; R 3 , R 66 , R 67 , R 81 , R 85 and R 89 are each independently hydrogen, C j -Cgalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, NR 56 R S7 , phenyl or benzyl ; R 4 , R 18 , R 19 and R 65 are each independently hydrogen, Ci-Cgalkyl, C 3 -Cgalkenyl, C 3 -C 6 alkynyl, C 1 -C 4 haloalkyl, C(0)R 58 , C(S)R 59 or benzyl; R 5 and R 72 are each independently C- L -Cgalkyl, C x -Cghaloalkyl, NRg 0 R 61 , imidazole or indazole; " ■ 6 » "ll ' '" • 12' "14 ' "1.5' 20 ' "21' "22' "25' "28' "29' "31' "32' "33' R 3S , R 45 , R 46 , R 63 and R 80 are each independently hydrogen or C 1 -C 4 alkyl; R 7 is hydrogen, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, benzyl, or C x -C 4 alkyl optionally substituted with cyano or C(0)R 62 ; R 8 and R 27 are each independently hydrogen, C x -C 4 alkyl or C 1 -C 4 alkoxy; R 9 and R 90 are each independently C x -Cgalkyl; R 10 is hydrogen, Ci-Cgalkyl, phenyl or benzyl; R 13 , R 24 and R 36 are each independently hydrogen, or halogen; R 23 is hydrogen or NR 63 R 64 ; R 34 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; R 37 is hydrogen, C x -C 4 alkyl or C 2 -C 8 alkoxyalkyl; R 38 and R 39 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C ε alkenyl or C 3 -C 3 alkynyl; R 40 , R 41 and R 42 are each independently hydrogen, halogen, cyano, OR 65 , C(0)Rg 6 , C(S)R 67 , C0 2 R 68 , C(=NOR S9 ) , a C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl group, wherein each group is optionally substituted with any combination of one to six halogen atoms, one to three C x -C 10 - alkoxy groups, one or two C- L -Cghaloalkoxy groups, one or two NR 70 R 71 groups, one or two S(0) q R 72 groups, one or two cyano groups, one or two C 3 -C 7 cycloalkyl groups, one OS0 2 R 73 group, one or two C(0)R 74 groups, one or two C0 2 R 75 groups, one or two C(0)SR 7S groups, one or two C(0)NR 77 R 78 groups, one to three 0R 79 groups, one or two P(O) (OR 80 ) 2 groups, one 1, 3-dioxolane optionally substituted with one to three C 1 -C 4 alkyl groups, or one 1,3-dioxane optionally substituted with one to three C 1 -C 4 alkyl groups, or phenyl or benzyl optionally substituted with any combination of one to three halogen atoms, one to three groups, one to three groups, one C 3 -C 7 cycloalkyl group, one C x - C 4 haloalkyl group, one C 1 -C 4 alkylthio group, one cyano group, one nitro group, one C(0)R 81 group, one C0 2 R 82 group, one OR 83 group, one SR 84 group, one C- L -Cgalkoxymethyl group, one hydroxymethyl group, one C 3 -C 8 alkenyloxymethyl group, or one C x - C 8 haloalkoxymethyl group ; R 43 / R 44 / R 47 and R 48 are each independently hydrogen, C 1 -C 4 alkyl, C x -C 4 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or C 3 -C 7 cycloalkyl, or R 43 and R 44 or R 47 and R 48 may be taken together with the atom to which they are attached to form a C 3 -C 7 cycloalkyl group; R 49 , R 50 and R 86 are each independently Ci-Cgalkyl, NR 93 R 94 , C 1 -C 4 haloakyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or benzyl; "51' "52' "53' "54' "55' "57' "58' "59' "60' "61' "62' "71' "73' "74' R 78 , R 87 and R 92 are each independently hydrogen, Ci-Cgalkyl, C 3 -C 7 cycloalkyl, C- L -Cghaloalkyl, C 3 -C ε alkenyl, C 3 -C 6 alkynyl, phenyl or benzyl; R 79 , R 83 and R 84 are each independently hydrogen, C(0)R 85 , S0 2 R 86 , C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 5 -C 8 cycloalkenyl, C 2 -Cgalkynyl, phenyl, benzyl, or C- L -C- Lo alkyl optionally substituted with one hydroxyl, benzyloxy, OC(0)R 87 , C0 2 R 88 , C(0)R 89 , C(OR 90 ) 2 , C(0)NR 91 R 92 or cyano group; R 93 and R 94 are each independently hydrogen, C 1 -C 4 haloalkyl, C 2 -Cgalkenyl, C 3 -C 8 cycloalkyl, C x -C 8 alkyl optionally substituted with one or two C x -C 4 alkoxy groups or one cyanoalkyl group, or benzyl or phenyl optionally substituted with any combination of one to three halogen atoms, one to three C 1 -C 4 alkyl groups, one to three C 1 -C 4 haloalkyl groups, one to three C x -C 4 alkoxy groups, one to three C 1 -C 4 haloalkoxy groups, one cyano group or one nitro group, and when R 93 and R 94 are taken together with the atom to which they are attached, they form a 5- to 12-membered monocyclic or fused bicyclic, heterocyclic ring optionally substituted with one or more groups independently selected from halogen, cyano, nitro, amino, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C x -C 4 haloalkoxy and C x -C 4 haloalkylsulf onyl groups ; and p and q are each independently 0 , 1 or 2 ; and the optical isomers, diastereomers and/or tautomers thereof . More preferred formula I herbicidal agents which may be prepared by the process of this invention are those wherein n is 1; Y is hydrogen or methyl ; G is CH 2 or a bond; G- . is CX S or N; G 2 is CX 4 or N; X x is hydrogen, fluorine or C 1 -C 3 alkyl optionally substituted with one epoxy group; X 2 is hydrogen, halogen NRR x , C0 2 R 2 , C(0)R 3 , OR 4 , S0 2 R 5 , S0 2 NR ε R 7 , C(R 8 ) (OR 9 ) 2 , C (R 10 ) =N0R 1X , C (R 12 ) =C (R 13 ) - C(OR 14 )=NOR 15 -, CH 2 0-NC0 2 R 16 , 1, 3-dioxolane optionally substituted with one C 1 -C 6 alkoxy group or one or two C 1 -C 4 alkyl groups , 1, 3-dioxolinone optionally substituted with one C 1 -C 6 alkoxy group or one or two C 1 -C 4 alkyl groups , or C 1 -C 4 alkyl optionally substituted with one C0 2 R 2 group and one halogen atom, and X 3 is hydrogen, halogen, C 1 -C 4 haloalkyl, C0 2 R 17 , cyano, C 1 -C 4 haloalkoxy, OR 18 or C 1 -C 4 alkyl, or when X- L and X 2 are taken together with the atoms to which they are attached, they may form a five- or six- membered ring wherein X X X 2 or X 2 X X is represented by: -OC(R 20 ) (R 21 )0-, -CH 2 S(0) p N(R 22 )-, -SC(R 23 )=N-, -CH=CH-CH(R X1 )0-, -OC(0)N-, -SC(R 24 )=N-, -ON (R 25 ) C (O) - , -OC(C0 2 R 26 )=CH-, -NC(R 28 )=C(SR 29 ) -, -CH=C (CO 2 R 30 ) 0- , -CH 2 CH(R 31 )0- or -OC (R 32 ) (R 33 ) C (0) - , or when X 2 and X 3 are taken together with the atoms to which they are attached, they may form a five- or six- membered ring wherein X 2 X 3 or X 3 X 2 is represented by: -NC(R 34 )=NC(S)-, -N(R 35 )N=C(R 36 )-, -N (R 37 ) C (R 38 ) =N- , -N(R 38 )C(0)CH 2 0-, -N(R 39 )C(0)CH=CH-, -S-N=C (R 40 ) - , 5 -0-N=C(R 41 )-, -N=N-N(R 42 )-, -C (R 43 ) (R 44 ) C (O) N (R 4S ) - or -N(R 46 )C(0)C(R 47 ) (R 48 )-; X 4 is hydrogen, halogen or OR 19 ; X 5 is hydrogen or halogen; R, R 64 , R 69 and R 77 are each independently hydrogen, 0 S0 2 R 49 or C x -C 4 alkyl; R X is hydrogen, SO 2 R 50 , C(0)R 51 , amino or C 1 -C 4 alkyl optionally substituted with C0 2 R 52 or C(0)R s3 ; independently hydrogen, C 3 -C 6 alkenyl or C 1 -C 4 alkyl 15 optionally substituted with C0 2 R 54 , morpholine or C(0)R 5S ; R 3 , R 66 , R 67 , R 85 and R 89 are each independently hydrogen, C 1 -C 4 alkyl or NR 56 R 57 ; R 4 , R 18 and R 19 are each independently hydrogen, 20 C 1 -C 4 alkyl, C x -C 4 haloalkyl, C(0)R S8 , C 3 -C 4 alkenyl or C 3 -C 4 alkynyl; R S6 is S0 2 R 49 ; R S7 is hydrogen or C x -C 4 alkyl; R s and R 72 are each independently NR 60 R 61 or indazole; • - • - 1 "6' "ll ' "12 ' "14' "15' "20' "21' "22' "25' "28' "29' "31' "32' "33' R 35 ' R 45 ' R 46 an d R eo are each independently hydrogen or methyl ; R 7 is C x -C 4 alkyl optionally substituted with cyano or C(0)R 62 ; 30 R 8 is hydrogen or C 1 -C 4 alkoxy; R 9 and R 90 are each independently C 1 -C 4 alkyl; R 10 is hydrogen or C 1 -C 3 alkyl; R 13 , R 24 and R 36 are each independently hydrogen or chlorine ; 35 R 23 is NR g3 R 64 ; R 34 is C x -C 3 haloalkyl; R 37 is C 2 -C 4 alkoxyalkyl; R 38 and R 39 are each independently C 1 -C 3 haloalkyl, C 1 -C 3 alkyl or propargyl; R 40 , R 41 and R 42 are each independently hydrogen, C(0)Rg 6 , C(S)R 67 , C0 2 R 68 , C(=NOR 69 ), C 1 -C 3 alkyl optionally substituted with any combination of one or two halogen atoms, one or two C 1 -C 3 alkoxy groups, one or two C 1 -C 3 haloalkoxy groups, one S0 2 R 72 group, one or two cyano groups, one C 3 -C 5 cycloalkyl group, one OS0 2 R 73 group, one C(0)R 74 group, one C0 2 R 7S group, one C(0)SR 76 group, one C(0)NR 77 R 78 group, one to two OR 79 groups, one P(O) (OR 80 ) 2 group, one 1,3- dioxolane group or one 1,3 -dioxane group, or phenyl optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR 83 group; R 43 ' R 44 ' R 47 an( R 48 are e ch independently hydrogen or methyl, or R 43 and R 44 or R 47 and R 48 may be taken together with the atom to which they are attached to form a cyclopropyl group; R 49 / R 50 and R 86 are each independently C 1 -C 4 alkyl or NR 93 R 94 ; R 51 ' R 52 ' R 53 ' R 54 ' R 55 ' R 58 ' R 60 ' R 61 ' R 62 ' R 73 ' R 74 ' R 78 a ^ R g7 are each independently hydrogen, C x -C 4 alkyl or C 1 -C 4 halo- alkyl ; R 79 and R 83 are each independently hydrogen, C (0) R 8S , S0 2 R 86 , C 1 -C 4 haloalkyl , C 3 -C 4 alkenyl or C 1 -C 3 alkyl substituted with one OC (0) R 87 , C0 2 R 88 , C (0) R 89 , C (OR 90 ) 2 or cyano group ; R 93 and R 94 are each independently hydrogen or Ci-Cgalkyl ; and p is 0 , 1 or 2 . The process of the present invention is especially useful for the preparation of 6- (trifluoromethyl) uracil compounds having the structural formula VI (VI) wherein Y is hydrogen or methyl; X 5 is hydrogen or halogen; R 40 is hydrogen, C(0)Rg 6 , C(S)R 67 , C0 2 R ε8 , C 1 -C 3 alkyl optionally substituted with any combination of one or two halogen atoms, one or two C 1 -C 3 alkoxy groups, one or two C 1 -C 3 haloalkoxy groups, one S0 2 R 72 group, one or two cyano groups, one C 3 -C 5 cycloalkyl group, one OS0 2 R 73 group, one or two OR 79 groups, one P(O) (OR 80 ) 2 group, one 1, 3-dioxolane group or one 1,3 -dioxane group, or phenyl optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR 83 group; R- R c R 85 and R 89 are each independently hydrogen, C x -C 4 alkyl or NR S gR 5, 7 ' ^56 is S0 2 R 49 ; R, is hydrogen or C 1 -C 4 alkyl ; R ■ ,49 and R 86 are each independently C x -C 4 alkyl or NR 93 R 94 ; Re and R 94 are each independently hydrogen or C 1 -C 8 alkyl ; R, and R 88 are each independently hydrogen, C 3 -C 3 alkenyl or C 1 -C 4 alkyl optionally substituted with C0 2 R 54 , morpholine or C (0) R S5 ; R. R, R 60 ' R c R 73 and R 87 are each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; R 72 is NR 60 R S1 or indazole; R 79 and R 83 are each independently hydrogen C(0)R 8s , S0 2 R 86 , C 1 -C 4 haloalkyl, C 3 -C 4 alkenyl or C 1 -C 3 alkyl substituted with one OC(0)R 87 , C0 2 R 88 , C(0)R 89 , C(OR 90 ) 2 or cyano group; R 80 is hydrogen or methyl; and R 90 is C 1 -C 4 alkyl. Exemplary of halogen hereinabove are fluorine, chlorine, bromine and iodine. The terms ξ$ halomethyl§ , g C 1 -C 4 haloalkylg , g , g C x -C 3 haloalkoxyg , ξ§ C x -C 4 haloalkoxy§ and § C 1 -C 8 haloalkoxymethyl§ are defined as a methyl, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 1 -C 4 alkoxy or C 1 -C 8 alkoxymethyl group substituted with one or more halogen atoms. In formula I above, alkali metals include sodium, potassium and lithium, and alkaline earth metals include calcium and magnesium. Organic ammonium cations suitable for use in the present invention include, but are not limited to, a group consisting of a positively charged nitrogen atom joined to from one to four aliphatic groups, each containing from one to sixteen carbon atoms. In formula I above, 5- to 12-membered monocyclic or fused bicyclic, heterocyclic rings include, but are not limited to, benzimidazole, imidazole, imidazoline-2-thione, indole, isatoic anhydride, morpholine, piperazine, piperidine, purine, pyrazole, pyrrole, pyrrolidine and 1, 2, 4-triazole rings wherein each ring is optionally substituted with one or more groups independently selected from halogen, cyano, nitro, amino, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, or C 1 -C 4 halo- alkylsulfonyl groups . Starting formula II carbamate compounds may be prepared by reacting a β-amino-β- (perfluoroalkyl) acrylate compound having the structural formula VII C ι F r 2n+l C ° 2 Z ι / NH (VII ) wherein n, Y and Z 1 are as described hereinabove with a base and a chloroformate compound having the structural formula VIII C1C0 2 Z (VIII) wherein Z is as described hereinabove. Formula II carbamate compounds may also be prepared according to the procedure described in Tetrahedron Letters, No.4, pages 243-246 (1976) . Formula VII β-amino-β- (perfluoroalkyl) acrylate compounds are known in the art and may be prepared according to the procedures described in U.S. 5,777,154; Journal of Heterocyclic Chemistry, 9, pages 513-522 (1972) ; and Institute of Chemistry, Urals Scientific Center, Academy of Sciences of the USSR, Sverdlovsk, pages 1442- 1447 (1987) - English translation of Zhurnal Organicheskoi Khimii, 22(8), pages 1603-1609 (1986). Chloroformate compounds of formula VIII are known in the art and may be prepared by conventional procedures . In addition, certain formula VIII chloroformate compounds are commercially available. Amine compounds having the structural formula Ilia (Ilia) wherein X 1# X s and R 40 are as described hereinabove, may be prepared, as shown in Flow Diagram I, by cyclizing a ketone of formula IX with sulfur and ammonium hydroxide or ammonia to form a nitrobenzisothiazole of formula X, and reducing the formula X compound using conventional reducing agents such as iron in acetic acid. FLOW DIAGRAM I (IX) (X) [H] (Ilia) Starting amine compounds having the structural formula Illb (Illb) wherein X 17 X 5 and R 41 are as described hereinabove, may be prepared, as illustrated in Flow Diagram II, by reacting a ketone of formula XI with hydroxylamine hydrochloride optionally in the presence of sodium acetate to form an oxime of formula XII, cyclizing the formula XII compound with a base such as potassium hydroxide to form a nitrobenzisoxazole of formula XIII, and reducing the formula XIII compound using conventional reducing agents such as tin (II) chloride in acetic acid. FLOW DIAGRAM II (XI) NH 2 OH • HC1 (XII) FLOW DIAGRAM II (cont.) Base (XIII) [H] (Illb) Alternatively, formula XIII nitrobenzisoxazole compounds may be prepared, as shown in Flow Diagram III, by reacting a ketone of formula XIV with hydroxylamine hydrochloride optionally in the presence of a base such as sodium acetate to form an oxime of formula XV, cyclizing the formula XV compound with 1, 1 ' -carbonyldiimidazole in the presence of a base such as triethylamine to form a benzisoxazole of formula XVI, and nitrating the formula XVI compound using conventional methods such as a nitric acid/sulfuric acid mixture. FLOW DIAGRAM III NH 2 OH HC1 (XVI ) HN0 3 /H 2 S0 4 (XII I ) Intermediate compounds of formulas X and XIII wherein R 40 and R 41 are 0R 6S may be prepared, as shown in Flow Diagram IV, by nitrating a benzisoxazol-3-ol or benzisothiazol-3-ol of formula XVII with a conventional nitrating agent such as a nitric acid/sulfuric acid mixture to form a 5- nitrobenzisoxazol-3-ol or 5-nitrobenzisothiazol-3-ol of formula XVIII, and reacting the formula XVIII compound with an electrophile of formula XIX in the presence of a base such as potassium carbonate. FLOW DIAGRAM IV (XVII) (J = 0 or S) (XVIII) Base XR S5 (XIX) (X = Cl, Br or I) Formula X and XIII intermediate compounds wherein R 40 and R 41 are Cl or Br may be prepared, as shown in Flow Diagram V, by reacting a 5-nitrobenzisoxazol-3-ol or 5- nitrobenzisothiazol-3-ol of formula XVIII with phosphorous oxychloride, phosphorous oxybromide or phosphorous pentabromide . FLOW DIAGRAM V (xviii; (J = 0 or S) P0C1 3 , POBr 3 or PBr 3 Other methods for the preparation of formula IIla and Illb amine compounds will become apparent from the examples set forth below. In addition, certain compounds of formulas Ilia, Illb, X and XIII may be converted into other compounds of formulas Ilia, Illb, X and XIII by using conventional procedures known to those skilled in the art . Other formula III amine compounds are known in the art and may be prepared according to the procedures described in EP 561319-A; EP 540023-A; EP 545206-A; EP 542685-A; EP 473551-A; EP 476697-A; EP 489480-A; EP 496595-A; EP 420194-A; EP 648749-A; EP 705829-A; EP 714602-A; JP 9241245; JP 9301973; U.S. 5,169,430; U.S. 5,310,723; U.S. 5,324,854; U.S. 5,391,541; U.S. 5,399,543; U.S. 5,484,763; U.S. 5,523,278; U.S. 5,602,077; U.S. 5,661,108; WO 93/14073; WO 94/10155; WO 94/24128; WO 91/07393 WO 91/107392; WO 95/04461; WO 95/05079; WO 95/05080 WO 95/17096 WO 95/25725; WO 95/29168, WO 95/32952 WO 95/33746 WO 96/02518; WO 96/08151, WO 96/14315 WO 96/28442 WO 96/34859; WO 96/35679, WO 97/01541 WO 97/01542 WO 97/05118; WO 97/07105 WO 97/08170 WO 97/08171 WO 97/08953; WO 97/12884 WO 97/12886 WO 97/29094 WO 97/29105; WO 97/34484 WO 97/35845 WO 97/42176 WO 97/42188; WO 97/45418, WO 97/47607 WO 98/02422 WO 98/06706; WO 98/08824, WO 98/27057 WO 98/27067 WO 98/27082; and WO 98/27088, among others . In order to facilitate a further understanding of this invention, the following examples are presented primarily for the purpose of illustrating more specific details thereof . The scope of the invention should not be deemed limited by the examples but encompasses the entire subject matter defined in the claims . EXAMPLE 1 Preparation of Ethyl 3 - [ (ethoxycarbonyl) aminol -4,4,4- trifluorocrotonate, (Z) - A solution of 3-amino-4 , 4,4-trifluorocrotonate (18.3 g, 100 mmol) in N,N-dimethylformamide (30 mL) is added dropwise to a stirred mixture of sodium hydride (60% in mineral oil, 9.6 g, 240 mmol) in N,N-dimethyIformamide (20 mL) at 0°C under nitrogen. Upon cessation of the evolution of hydrogen gas, a solution of ethyl chloroformate (13.02 g, 120 mmol) in anhydrous ether (30 mL) is added at 0°C over 30 minutes. The resultant reaction mixture is then stirred at room temperature for one hour, and quenched with water and ethyl acetate . The resultant mixture is extracted with ethyl acetate. The organic extract is washed sequentially with water and aqueous 2 N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. Fractional distillation of the residue under reduced pressure gives the title product as a liquid (18 g, 70.5% yield, bp 95-97°C (4.5 mm)) which is identified by 1 H and 19 F NMR spectral analyses. EXAMPLE 2 Preparation of Ethyl 3- [ (N-ethoxycarbonyl) -N- ethylaiαino] -4, 4,4-trifluorocrotonate, (Z) - A solution of 3 -methylamino-4 , 4, 4 -trifluorocrotonate (9.86 g, 50 mmol) in N,N-dimethylformamide (30 mL) is added dropwise to a stirred mixture of sodium hydride (60% in mineral oil, 4.5 g, 112 mmol) in N,N-dimethylformamide (30 mL) at -10°C under nitrogen. The resultant mixture is stirred at 0°C for 2 hours, treated with a solution of ethyl chloroformate (8.14 g, 75 mmol) in anhydrous ether (40 mL) at -10°C over 40 minutes, stirred at room temperature overnight, and quenched with water and ethyl acetate. The resultant mixture is extracted with ethyl acetate. The organic extract is washed sequentially with water and aqueous 2 N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. Fractional distillation of the residue under reduced pressure gives the title product as a liquid (6.5 g, 48.3% yield, bp 60-62°C (0.2 mm)) which is identified by X H and 19 F NMR spectral analyses . EXAMPLE 3 Preparation of 3-Isopropyl-6- (trifluoromethyl) -2 , 4- (1H.3H) -pyrimidinedione 3 ^^^C0.C 2 H 5 ,CH, / 3 HN-s. + H 2 N— ∞ 2 C 2 H 5 CH 3 0 CH 3 A stirred mixture of ethyl 3- [ (ethoxycarbonyl) amino] - 4, , 4-trifluorocrotonate, (Z) - (2.04 g, 8 mmol), isopropylamine (0.567 g, 9.6 mmol), and 1,8-diazabi- cyclo [5,4, 0]undec-7-ene (DBU, 1.46 g, 9.6 mmol) in xylene (15 mL) is heated at 100°C for 3 hours, cooled, and diluted with ethyl acetate. Water is added, and the resultant aqueous mixture is extracted with ethyl acetate . The organic extracts are combined, washed sequentially with water and aqueous 2 N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a solid. The solid is crystallized from methanol/water to give the title product as a solid (1.08 g, 61% yield) which is identified by X H and 19 F NMR spectral analyses . EXAMPLE 4 Preparation of 3- [3- (β-Methoxy-m-tolyl) -1,2-benziso- thiazol-5-yl) -6- (trifluoromethyl) -2 , 4 (1H, 3H) - pyrimidinedione A mixture of ethyl 3- [ (ethoxycarbonyl) amino] -4,4, 4- trifluorocrotonate, (Z) - (2.04 g, 8 mmol), 5-amino-3- (6- methoxy--7?-tolyl) -1, 2-benzisothiazole (2.59 g, 9.6 mmol) and 1, 8-diazabicyclo [5,4, 0] undec-7-ene (DBU, 1.46 g, 9.6 mmol) in xylene (15 mL) is heated at 110°C for 6 hours, cooled, and quenched with ethyl acetate and water. The resultant mixture is extracted with ethyl acetate . The organic extracts are combined, washed with aqueous 2 N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a foam. Flash chromatography of the foam using silica gel and a 3:7 ethyl acetate/hexanes solution gives the title product as a solid (2.5 g, 72% yield) which is identified by X H and 19 F NMR spectral analyses. EXAMPLE 5 Preparation of 2 ' -Chloro-2-methθ3cy-5-methyl-5' nitrobenzophenone CH. A mixture of aluminum chloride (33.3 g, 25.0 mmol) in methylene chloride is cooled to about 5 °C, treated over one hour with p-methylanisole (31.6 g, 25.0 mmol) while maintaining the reaction mixture temperature below 10 °C, treated over 20 minutes with a solution of 2-chloro-5- nitrobenzoyl chloride (50.0 g, 22.7 mmol) in methylene chloride while maintaining the reaction mixture temperature below 10 °C, warmed to and stirred at room temperature for 60 minutes, and poured onto ice. The resultant aqueous mixture is treated with concentrated hydrochloric acid (50 mL) and extracted with methylene chloride. The organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow solid. After placing the solid in a Kugelrohr apparatus at 40 °C to remove residual p-methylanisole, the title product is obtained as a beige solid (68.8 g, 99.1%) which is identified by NMR spectral analyses. Using essentially the same procedure, the following compounds are obtained: Cl H Cl H H I H H OCH 3 115-116.5 Cl H H H CH 3 H OCH 3 Cl H H H C 2 H 5 H H Cl H H CH 3 CH 3 H OCH 3 Cl H H H OCH 3 H H 108-112 Cl H H C 2 H B H H OCH 3 98-99.5 Cl H H H OCH 3 H CH 3 91-92 Cl H H H CH 3 H H 95.5-96.5 Cl H H H SCH 3 H H 127-128 Cl H H H CH 3 H OCH 3 91-92.5 Cl H H H C 2 H 5 H H Cl H H H Cl H H 88.5-90.5 Cl H H H F H H 68-69.5 Cl H H Cl H H OCH 3 124-126 Cl H H OCH 3 H H OCH 3 71-73 Cl H H H OCH 3 H OCH 3 98-100 Cl H H CH 3 CH 3 H OCH 3 127-129 Cl H H H Cl H OCH 3 96-99 Cl H CH 3 H CH 3 H OCH 3 108.5-110 Cl H H H H CH, OCH, 71-74 Cl H H H N(CH 3 )- H H S0 2 CH 3 Cl H H CH 3 Cl H OCH 3 126-128 Cl H H CH 3 H CH 3 OCH 3 110-112 Cl H CH 3 CH 3 CH 3 H OCH 3 104-106 Cl H H CH(CH 3 ) 2 H H OCH 3 69-71 Cl H H CH 3 H H H Cl H H H H H CN Cl H H H H H OCH 3 Cl H H OCH 3 H H H Cl H H F H H OCH 3 Cl H H H F H OCH 3 Cl H H H H H SCH 3 Cl H H H H H CH 3 Cl H H H H H F Cl H H SCH 3 H H H Cl H H H OCH 3 H H Cl H H -(CH 2 ) 3 - H OCH 3 Cl F H H H H H F F H CH 3 H H OCH 3 EXAMPLE 6 Preparation of 3- (6-Methoxy-m-tolyl) -5-nitro-l, 2' benzisothiazole Ammonium hydroxide (350 mL of a 30% solution, 270 mmol) is added to a mixture of 2 ' -chloro-2-methoxy-5- methyl-5 ' -nitrobenzophenone (68.7 g, 22.5 mmol) and sulfur (7.57 g, 23.6 mmol) in N,N-dimethylformamide . The resultant reaction mixture is stirred at 80 °C for 19.5 hours, cooled to 40 °C, treated with additional ammonium hydroxide (50 mL of a 30% solution) , stirred at 80 °C for 25 hours, cooled, and poured onto ice. The resultant aqueous mixture is filtered to obtain the title product as a yellow solid (63.5 g, 93.9%) which is identified by NMR spectral analyses . Using essentially the same procedure, the following compounds are obtained: H H CH 3 H OCH 3 201-203 H CH 3 CH 3 H OCH 3 199-200 H CH 3 H H H 116.5-117.5 H H Cl H OCH 3 229-231 H H H CH 3 OCH 3 134-136 H H H H CN 187.5-189 H H H H OCH 3 193-198 H H OCH 3 H H 201-203 H OCH 3 H H H 174-175 H F H H OCH 3 224-226 H C 2 H 5 H H OCH 3 153-154.5 H H CH 3 H H 188-189 H H N(CH 3 )S0 2 CH 3 H H H CH 3 Cl H OCH 3 230-234 H I H H OCH 3 H H SCH 3 H H 177.5-178.5 H H OCH 3 H CH 3 131-135 H H F H H 226-228 H H Cl H H 217.5-219 H H F H OCH 3 224-225 H H H H SCH 3 114.5-115.5 H H CH 3 H OCH 3 201-203 H OCH 3 H H OCH 3 195-196 H H H H CH 3 145-146 H H H H F 181-182 H H OCH 3 H OCH 3 171-172.5 H SCH 3 H H H 139-140.5 H CH 3 H CH 3 OCH 3 CH 3 CH 3 CH 3 H OCH 3 H CH(CH 3 ) 2 H H OCH 3 H H CH 3 CH 3 OCH 3 H -(CH 2 ) 3 - H OCH 3 EXAMPLE 7 Preparation of 3-Methyl-5-nitro-1, 2-benzisothiazole 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. Using essentially the same procedure, the following compounds are obtained: H C 2 H 5 R. EXAMPLE 8 Preparation of 5-Amino-3- (6-methoxy-fli-tolyl) -1,2- benzisothiazole A mixture of 3- (6-methoxy-m-tolyl) -5-nitro-l, 2- benzisothiazole (63.0 g, 0.210 mol), 5% acetic acid (1.52 L, 1.21 mol) and ethyl acetate (975 mL) is heated to 65 °C, treated portionwise with iron powder (58.6 g, 1.05 mol) , stirred at 65 °C, and filtered through quartz filter paper. The filtrate phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as an orange oil (55.7 g, 98.1%) which is identified by NMR spectral analyses . Using essentially the same procedure, the following compounds are obtained: X 5 mp H H H CN 118.5-120 H CH 3 112-113.5 H C 2 H S OCH. OCH, SCH. χ 5 mp p OCH, X. °C OCH, H C(CH 3 ) 2 C0 2 C 2 H 5 H OCH 2 CN H OCH 3 H OCH(CH 3 ) 2 H OCH 2 CH=CH 2 H OCH 2 C≡CH H OCH 2 C0 2 CH 3 EXAMPLE 9 Preparation of 2-Chloro-2' -methoxy-5' -methyl-5- nitrobenzophenone, oxime A mixture of 2-chloro-2 ' -methoxy-5 ' -methyl-5-nitro- benzophenone (90.0 g, 0.294 mol) in ethanol is treated with a solution of hydroxylamine hydrochloride (102.3 g, 1.47 mol) in water, refluxed overnight, and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried in a hot vacuum oven overnight to give the title product as a white solid (84.2 g) which is identified by H NMR spectral analysis. Using essentially the same procedure, the following compounds are obtained: χ 5 H 2 w 3 mp °C H OCH 3 H H 173-178 H H H H 143-145 H H OCH 3 H 191-192.5 H OCH 3 H F H H OCH 2 C0 2 CH 3 H 150-155 H OCH 3 H CH 3 185.5-186.5 F OCH, H CH, and mp 165-167°C EXAMPLE 10 Preparation of 3- (6-Methoxy-m-tolyl) -5-nitro-l,2- benzisoxazole A mixture of 2-chloro-2 ' -methoxy-5 ' -methyl-5-nitro- benzophenone, oxime (84.0 g, 0.262 mol) in ethanol is warmed to 65 °C, treated with 150 mL of 10% potassium hydroxide solution over 25 minutes, heated to 78 °C over one hour, cooled, and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water, dried, recrystallized from N,N- dimethylformamide, washed sequentially with N,N-dimethyl- formamide and ethanol, and dried in a vacuum oven at 80 °C to give the title product as a solid (mp 225-226 °C) which is identified by X H NMR spectral analysis. Using essentially the same procedure, the following compounds are obtained: W El H 2 mp °C H OCH 3 H H 170- -171 H H H H 138- -139 H H H OCH 3 205- -207 F OCH, CH, H and mp 84.5-86.5°C EXAMPLE 11 Preparation of 5-Amino-3- (6-methoxy-m-tolyl) -1, 2- benzisoxazole and 5-Amino-4-chloro-3- (6-methoxy-m-tolyl) 1, 2-benzisoxazole A mixture of 3- (6-methoxy-Jτι-tolyl) -5-nitro-l, 2- benzisoxazole (20.0 g, 0.0703 mol) in acetic acid (380 mL) is warmed, treated with a warm solution of tin (II) chloride dihydrate (47.4 g, 0.210 mol) in concentrated hydrochloric acid (110 mL) , refluxed for one hour, cooled to 10 °C, and concentrated in vacuo to obtain a gum. The gum is added to water with stirring to obtain a slurry. The slurry is treated with 80 g of 50% sodium hydroxide solution, stirred at 60 °C to 80 °C over one hour, cooled, and decanted to obtain a residue . A mixture of the residue in ethanol is treated with potassium hydroxide (10 g) , heated overnight, cooled to room temperature, neutralized with hydrochloric acid, and concentrated in vacuo to obtain a residue. The residue is diluted with ethyl acetate and filtered. The filtrate is concentrated in vacuo and chromatographed using silica gel and a 2% ethyl acetate in methylene chloride solution to give the title products as semi-solids which are identified by elemental and mass spectral analyses. Using essentially the same procedure, the following compounds are obtained: H CH 3 H Cl H OCH 2 C0 2 CH 3 H OCH (CH 3 ) 2 H OCH ( CH 3 ) C0 2 CH 3 F OCH 2 C0 2 CH 3 H OCH, EXAMPLE 12 Preparation of m-Fluorophenyl acetate A solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride is cooled to 0 °C to 5 °C, treated with pyridine (75.0 mL, 0.930 mol), stirred for several minutes, treated dropwise with acetyl chloride (66.0 mL, 0.930 mol) while maintaining the reaction mixture temperature below 17 °C, stirred at ice-bath temperature for two hours, warmed to room temperature, and poured into an ice-water mixture. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as a yellow oil which is identified by 1 H NMR spectral analysis. EXAMPLE 13 Preparation of 4' -Fluoro-2' -hydroxyacetophenone ui-Fluorophenyl acetate (123 g, 0.798 mol) is cooled with an ice-bath, treated portionwise with aluminum chloride (150 g, 1.12 mol), stirred at 190 °C for one hour, and cooled to obtain a solid. A mixture of ice, water and hydrochloric acid, and methylene chloride are added to the solid. The resultant mixture is stirred for several minutes, and the phases are separated. The organic phase is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product (99.0 g) which is identified by X H NMR spectral analysis . EXAMPLE 14 Preparation of 4 ' -Fluoro-2 7 -hvdroxyacetophenone, oxime A mixture of 4 ' -fluoro-2 * -hydroxyacetophenone (99.0 g, 0.640 mol), hydroxylamine hydrochloride (89.0 g, 1.28 mol), and sodium acetate (79.0 g, 0.960 mol) in methanol is refluxed for one hour and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid. The solid is dissolved in methylene chloride, and the resultant organic solution is dried over anhydrous magnesium sulfate, concentrated in vacuo, diluted with hexanes, and filtered to give the title product as a solid (55.0 g, mp 112-114 °C) which is identified by X H NMR spectral analysis. EXAMPLE 15 Preparation of 6-Fluoro-3-methyl-l, 2-benzisoxazole A mixture of 4 ' -fluoro-2 ' -hydroxyacetophenone, oxime (47.0 g, 0.278 mol) in tetrahydrofuran is heated to just under reflux, treated with a solution of 1, 1 ' -carbonyldiimidazole (55.0 g, 0.340 mol) and triethylamine (39.0 g, 0.390 mol) in tetrahydrofuran, refluxed for one hour, cooled, concentrated in vacuo, and poured into an ice-water mixture. The resultant aqueous mixture is extracted with ether. The organic extracts are combined, washed sequentially with saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil . Column chromatography of the oil using silica gel and a methylene chloride/hexanes solution (1:1) gives the title product as a yellow oil which is identified by 1 H NMR spectral analysis. EXAMPLE 16 Preparation of 6 -Fluoro- 3 -methyl- 5 -nitro-1 , 2 -benzisoxazole A mixture of 6-fluoro-3 -methyl-1, 2-benzisoxazole (23.5 g, 0.156 mol) in concentrated sulfuric acid is cooled with an ice-bath, treated dropwise with 90% nitric acid (8.50 mL) while maintaining the reaction mixture temperature below 15 °C, stirred for one hour at ice-bath temperature, treated with additional 90% nitric acid (5.80 mL) , warmed to and stirred at room temperature overnight, and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is air-dried and dissolved in methylene chloride. The resultant organic solution is dried over anhydrous magnesium sulfate, diluted with hexanes, and filtered to give the title product as a purple solid which is identified by X H NMR spectral analysis. Using essentially the same procedure, the following compounds are obtained: x 5 H Cl F EXAMPLE 17 Preparation of Methyl I (5-nitro-l,2-benzisoxazol-3- yl) oxy] cetate A mixture of 5-nitro-l, 2-benzisoxazol-3-ol (3.90 g, 0.0220 mol) and potassium carbonate (4.17 g, 0.0300 mol) in N,N-dimethylformamide is stirred for 30 minutes, treated with methyl bromoacetate (3.96 g, 0.0260 mol), stirred overnight at room temperature, and poured into an acidic ice-water mixture. The resultant aqueous mixture is extracted with ethyl acetate . The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow oil . Column chromatography of the oil using silica gel and a (1:1) to (4:1) methylene chloride/hexanes gradient gives the title product as a white solid (2.80 g, mp 72-73.5 °C) which is identified by NMR spectral analyses . Using essentially the same procedure, the following compounds are obtained: χ 5 --Ml mp °C H OCH(CH 3 ) 2 81- -83 H OCH 2 CH=CH 2 70- -72 H OCH 3 101.1 5-103 Cl OCH(CH 3 )C0 2 CH 3 98- 100 F OCH 2 C0 2 CH 3 104- -106 EXAMPLE 18 Preparation of 3-Chloro-5-nitro-l,2-benzisoxazole A mixture of 5-nitro-l, 2-benzisoxazol-3-ol (4.00 g, 0.0220 mol) and phosphorus oxychloride (40.0 L, 65.8 g, 0.429 mol) is placed in a glass bomb, heated at 150-155 °C for two hours, cooled overnight, concentrated in vacuo, diluted with methylene chloride, and brought to about pH 8 with sodium hydrogen carbonate solution. The phases are separated. The organic phase is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and a methylene chloride/hexanes solution (1:1) gives the title product as an amber oil which is identified by NMR spectral analysis . EXAMPLE 19 Preparation of 2 -Chloro-2 ' -methoxy- 5 -nitrobenzophenone A solution of 2-bromoanisole (27.9 g, 145 mmol) in diethyl ether is cooled to -70 °C, treated with butyllithium (64.0 mL, 160 mmol), stirred at -70 °C for one hour, treated with 0.5 M zinc chloride in tetrahydrofuran solution (320 mL, 160 mmol) , stirred for one hour at -70 °C, warmed to about 0 °C, and concentrated in vacuo to obtain a yellow- green oil . A solution of the oil in tetrahydrofuran is treated sequentially with tetra is (triphenylphosphine) palladium (0) (5.00 g, 4.35 mmol) and a solution of 2-chloro-5-nitrobenzoyl chloride (35.0 g, 159 mmol) in tetrahydrofuran, stirred for three days, and poured into 10% hydrochloric acid. The resultant aqueous mixture is extracted with methylene chloride . The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a semi-solid. The solid is triturated with diethyl ether to give the title product as a yellow solid which is identified by NMR spectral analyses . Using essentially the same procedure, the following compounds are obtained: W, W, W 4 mp °C H Cl H OCH 3 96 -99 H H CH 3 OCH 3 71 -74 F H H OCH 3 Cl H H OCH 3 12 -126 OCH 3 H H OCH 3 71 -73 H OCH 3 H OCH 3 98- 100 H F H OCH 3 H H CH 3 H 65-' 66.5 H H SCH 3 H 87 -88 H H H F 118 -120 H H H CH 3 78- 79.5 H H H SCH 3 123- 124.5 H F H H H H OCH 3 H H H H OCH 3 H CH, CH, OCH, EXAMPLE 20 Preparation of 2-Chloro-2 -methoχy-5-nitrobenzhvdrol A solution of 2-bromoanisole (50.0 g, 0.267 mol) in ether is added portionwise to a mixture of magnesium (7.10 g, 0.293 mol) in ether. After the addition is complete, the reaction mixture is heated at reflux for one hour, diluted with ether, cooled to 0 °C, treated with a solution of 2-chloro-5-nitrobenzaldehyde (39.0 g, 0.210 mol) in tetrahydrofuran, warmed to room temperature, and diluted with an ice-water mixture. After acidifying the aqueous mixture with hydrochloric acid (pH 2 - pH 3) , the organic phase is separated and the aqueous phase is extracted with ether. The organic extracts are combined, washed sequentially with 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a brown gum. Using essentially the same procedure, the following compounds are obtained: W W, W. OCH 3 H OCH 3 CH, H OCH 3 F H OCH, H OCH, H EXAMPLE 21 Preparation of 2-Chloro-2 / -methoxy-5-nitrobenzophenone A solution of chromium (VI) oxide (91.0 g, 0.919 mol) in a water/acetic acid solution (1:4) is added portionwise to 2-chloro-2 ' -methoxy-5-nitrobenzhydrol (64.2 g, 0.219 mol) while maintaining the reaction mixture temperature at 25 °C to 35 °C. The reaction mixture is then stirred at 25 °C to 35 °C for one hour, cooled, diluted with water, and concentrated in vacuo to obtain a residue. The residue is diluted with water, and extracted with methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, mixed with silica gel (10 g) , and filtered. The filtrate is concentrated in vacuo to obtain an oil . A solution of the oil in a methanol/water solution is decolorized with charcoal and concentrated in vacuo to yield a residue. Column chromatography of the residue using silica gel and methylene chloride/hexanes solutions gives the title product as a white solid. Using essentially the same procedure, the following compounds are obtained: OCH 3 H OCH 3 CH, H OCH 3 109-111 F H OCH, 94-95 H OCH, H 79-81 EXAMPLE 22 Preparation of 2-Chloro-4-fluoro-5-nitrobenzoyl chloride 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), refluxed for 3 hours, cooled, and concentrated in vacuo to obtain the title product as an orange solid which is identified by NMR spectral analyses Following essentially the same procedure, but using 2, 4-difluoro-5-nitrobenzoic acid, 2 , 4-difluoro-5- nitrobenzoyl chloride is obtained as a brown oil. EXAMPLE 23 Preparation of 2 ' -Chloro-4' -fluoro-5' -nitroacetophenone + CHZnCl + Pd[P(C 6,H5J J3 4 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 (triphenylphosphine) 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 anhydrous 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 24 Preparation of 6-Amino-3-methyl-5-nitro-l, 2- benzisothiazole A mixture of 2 ' -chloro-4 ' -fluoro-5 ' -nitroacetophenone (12.0 g, 0.0552 mol), sulfur (1.77 g, 0.0552 mol), 30% ammonium hydroxide solution (100 mL, 0.856 mol), and methanol is placed in a steel bomb, heated at 85 °C overnight, cooled, treated with additional sulfur (0.270 g) and 30% ammonium hydroxide solution (50 mL) , heated at 85 °C overnight, cooled, filtered to remove solids, and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel, and 0%, 1% and 2% diethyl ether in methylene chloride solutions gives the title product as an orange solid (4.19 g, mp 189-191 °C) which is identified by NMR spectral analyses . Using essentially the same procedure, the following compound is obtained: EXAMPLE 25 Preparation of 6-Chloro-3-methyl-5-nitro-l,2- benzisothiazole A mixture of tert-butyl nitrite (3.30 mL, 0.0278 mol) and copper (II) chloride (2.98 g, 0.0222 mol) in aceto- nitrile is heated to 65 °C, treated portionwise with 6-amino-3-methyl-5-nitro-l,2-benzisothiazole (3.88 g, 0.0185 mol), stirred at 65 °C, cooled to room temperature, and poured into 20% hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with 20% hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and methylene chloride/hexanes solutions (1:1 and 3:1) gives the title product as a pale, yellow solid (2.54 g, mp 156-158 °C) which is identified by NMR spectral analyses. Using essentially the same procedure, the following compound is obtained: EXAMPLE 26 Preparation of 6-Fluoro-3-methyl-5-nitro-l,2- benzisothiazole A mixture of 6-chloro-3-methyl-5-nitro-l, 2- benzisothiazole (2.25 g, 9.80 mmol), potassium fluoride (2.85 g, 49.0 mmol), and 18-crown-6 (1.50 g, 5.70 mmol) in acetonitrile is heated in a sealed tube for 29 days, filtered to remove solids, and partially concentrated in vacuo to obtain a liquid. The liquid is diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a dark, brown solid. Flash column chromatography of the solid using silica gel and a 10% to 50% ethyl acetate in hexanes gradient gives a yellow solid containing two components. Flash column chromatography of the yellow solid using silica gel and a 50% to 70% methylene chloride in hexanes gradient gives the title product as a pale, yellow solid (0.870 g, mp 118-119 °C) which is identified by NMR spectral analyses . Using essentially the same procedure, the following compound is obtained: EXAMPLE 27 Preparation of 2.2 ' -Dithiobis [5-nitrobenzoic acid] A mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol is treated portionwise with potassium tert-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 28 Preparation of 5-Nitro-l, 2-benzisothiazol-3 (2H) -one 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-dichloroethane. 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 29 Preparation of 3-Chloro-5-nitro-l, 2-benzisothiazole 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 tributylamine (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-water 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 30 Preparation of Ethyl α-cvano- 5 -nitro-l , 2 -benziso- thiazole- 3 -acetate 1 ) C 2 H 5 0 " Na + CH 2 ( CN) C0 2 C 2 H 5 HC1 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 cyano- acetate (4.51 g, 0.0398 mol), stirred at room temperature for 30 minutes, treated with 3-chloro-5-nitro-l, 2-benz- isothiazole (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 31 Preparation of Ethyl 5-nitro-l,2-benzisothiazole-3- acetate C2H.5 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 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) . EXAMPLE 32 Preparation of 5-Nitro-l,2-benzisothiazole-3-aceto- nitrile A mixture of ethyl 5-nitro-l, 2-benzisothiazole-3- acetate (5.00 g, 17.2 mmol), water (1.00 mL) , and methyl sulfoxide (35.0 mL) is stirred at 107 °C for 24 hours, stirred at room temperature for two days, and poured into an ice-water mixture. The resultant aqueous mixture is stirred for two hours and filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a tan solid. EXAMPLE 33 Preparation of α,α-Dimethyl-5-nitro-l,2-benziso- thiazole-3 -acetonitrile A mixture of 5-nitro-l, 2-benzisothiazole-3-aceto- nitrile (1.29 g, 5.89 mmol) in N, N-dimethylformamide is cooled to -9 °C, treated with sodium hydride (1.00 g of a 60% dispersion in oil) , stirred at -3 °C for 20 minutes, treated with iodomethane (5.00 mL) , stirred at room temperature for four hours, and poured onto ice. The resultant aqueous mixture is treated with 10% hydrochloric acid and extracted with methylene chloride . The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium 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 yellow solid which is identified by NMR spectral analysis. EXAMPLE 34 Preparation of Ethyl α,α-dimethyl-5-nitro-l, 2-benz- isothiazole-3-acetate A mixture of α,α-dimethyl-5-nitro-l, 2-benzisothiazole- 3-acetonitrile (0.913 g, 3.69 mmol), water (0.450 mL) , concentrated sulfuric acid (4.55 mL) and ethanol (9.10 mL) is refluxed for one hour, cooled, and poured onto ice. The resultant aqueous mixture is neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride. The organic extract is washed with water, dried over anhydrous sodium 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 pale yellow crystals, spectral analysis . EXAMPLE 35 Preparation of 5-Amino-3-chloro-l,2-benzisothiazole 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 mL) , 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 36 Preparation of [ (5-Nitro-l,2-benzisothiazol-3-yl) oxy] acetonitrile CN A mixture of 5-nitro-l, 2-benzisothiazol-3 (2H) -one (17.5 g, 89.2 mmol) in N,N-dimethylformamide is treated with potassium carbonate (18.5 g, 134 mmol), stirred at room temperature for 30 minutes, treated with bromoaceto- nitrile (16.0 g, 133 mmol), stirred at room temperature overnight, and poured onto ice. The resultant aqueous mixture is acidified to pH 3 with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are 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 yellow solid (15.0 g, mp 123-124.5 °C) . Using essentially the same procedure, the following compounds are obtained: OCH, 108-109 mp OCH ( CH 3 ) 2 OCH 2 CH=CH 2 OCH 2 C≡CH 115-117 OCH 2 C0 2 CH 3 EXAMPLE 37 Preparation of 5-Nitro-l,2-benzisothiazole To a mixture of ammonium hydroxide (1000 ml) and N,N- dimethylformamide is added 2-chloro-5-nitrobenzaldehyde (300 g, 1.62 mol) and sulfur (54.4 g, 1.70 mol). The mixture is heated slowly to and stirred at 90 °C for one hour, cooled to room temperature, poured onto ice, and diluted with water. Filtration affords the title compound as a yellow solid (277.1 g, 94.9%). Using essentially the same procedure, but using 2'- chloro-5 ' -nitro-2-methyl-2-carboethoxypropiophenone, ethyl α,α-dimethyl-5-nitro-l, 2-benzisothiazole-3-acetate is obtained as a solid (mp 75-77°C) . EXAMPLE 38 Preparation of 3 - Chloro- 5 -nitro- l , 2 -benzisothiazole A suspension of 5-nitro-l, 2-benzisothiazole (271 g, 1.50 mol) in acetic acid is heated to 80 °C to form a solution. The heating source is removed and chlorine gas is added continuously over six hours at 70-80 °C until saturation of the mixture occurs. The mixture is cooled to room temperature and stirred overnight. Filtration affords the title compound as a yellow crystalline solid (237 g, 73.6%) which is identified by NMR spectral analysis. EXAMPLE 39 Preparation of 2 ' -Chloro-2-methyl-2-carboethoxy propiophenone A mixture of 2-chlorobenzoyl chloride (52.2 g, 0.298 mol), ethyl 2-bromoisobutyrate (58.2 g, 0.298 mol) and ether is added in portions to zinc foil (19.5 g, 0.298 mol) and the resultant mixture stirred at reflux for three hours and overnight at room temperature. The mixture is poured into cold, dilute sulfuric acid and the organic layer is washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a yellow oil. The oil is chromatographed on silica gel with hexanes: ethyl acetate to afford the title compound as a colorless oil (41.8 g, 55.1%). EXAMPLE 40 Preparation of 2 ' -Chloro-5 , -nitro-2-methyl-2- carboethoxypropiophenone To concentrated sulfuric acid (15.0 ml) at 5 °C is added 2 ' -chloro-2 -methyl-2-carboethoxypropiophenone (4.00 g, 0.01570 mol) followed by dropwise addition of concentrated nitric acid (90%, 0.740 ml, 0.0204 mol). After stirring 5 minutes, the mixture is poured onto ice and extracted with ethyl acetate . The organic layers are washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (3.90 g, 83.0%) which is identified by NMR spectral analysis. EXAMPLE 41 Preparation of 1-Benzothiophen-2 , 3 -dione 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 concentrated 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 42 Preparation of 1.2-Benzisothiazole-3-carboxamide To ammonium hydroxide (1.78 1) is added 1- 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 43 Preparation of 3-Cvano-5-nitro-l,2-benzisothiazole 2) POC1, A solution of 1, 2-benzisothiazole-3-carboxamide (12.0 g, 0.0674 mol) in concentrated sulfuric acid at 0-5 °C is treated dropwise with nitric acid (90%, 4.12 ml) such that the temperature does not exceed 10 °C, stirred one hour at 5 °C, and poured into ice water with vigorous stirring. The resultant suspension is filtered to obtain a solid. The solid is dried and recrystallized from acetonitrile to afford a white solid (10.0 g) which is treated with phosphorus oxychloride (60.0 ml). The resultant mixture is stirred at 90-100 °C for 90 minutes, cooled to room temperature, slowly poured into ice water with stirring, and filtered to obtain a solid. Recrystallization of the solid from methylene chloride : hexanes gives the title compound as an orange solid (8.00 g, 87.9%, mp 168-170 °C) which is identified by NMR and IR spectral analyses. EXAMPLE 44 Preparation of 3- (6-Methoxy-m-tolyl) -6-amino-5-nitro- 1 , 2 -benzisothiazole Ammonium hydroxide (330 ml) is added to a suspension of 2 ' ,4 ' -difluoro-2-methoxy-5-methyl-5 ' -nitrobenzophenone (60.0 g, 0.186 mol), sulfur (6.25 g, 0.195 mol) and N,N- dimethylformamide on an ice bath. The resultant mixture is allowed to warm to 35 °C, heated gradually to 81 °C over a two hour period, cooled to room temperature, and poured into water. The resultant solid is taken up in ethyl acetate and N,N-dimethylformamide, and washed with water. The organic layer is concentrated in vacuo to afford the title compound which is identified by NMR spectral analysis . EXAMPLE 45 Preparation of 3- (6-Methoxy-m-tolyl) -6-chloro-5-nitro- 1 , 2 -benzisothiazole nitrite + CuCl, A mixture of tert-butyl nitrite (5.90 g, 0.0571 mol), copper chloride (6.20 g, 0.0457 mol) and acetonitrile is heated to 65-75 °C, treated with 3- (6-methoxy-m-tolyl) -6- amino-5-nitro-l, 2-benzisothiazole (12.0 g, 0.0381 mol) over 10 minutes, stirred for two hours at 67-75 °C, treated with tert-butyl nitrite (1.50 ml) and copper chloride (1.00 g) , stirred 40 minutes at 67-75°C, cooled to room temperature, and diluted with ethyl acetate. The organic layer is washed with 10% hydrochloric acid and filtered. The filtrate is washed with water and concentrated in vacuo to afford the title compound as a solid (10.6 g, 83.1%) which is identified by NMR and IR spectral analyses. EXAMPLE 46 Preparation of 3- (6-Methoxy-m-tolyl) -6-fluoro-5-nitro- 1, 2-benzisothiazole A mixture of 3- (6-methoxy-m-tolyl) -6-chloro-5-nitro- 1, 2-benzisothiazole (7.30 g, 0.0218 mol), potassium fluoride (6.33 g, 0.109 mol) 18-crown-6 (2.31 g, 0.0872 mol) and sulfolane is stirred 19 hours at 154°C, cooled to room temperature, and poured into ice water. The resultant solid is filtered and chromatographed on silica gel with methylene chloride to afford a solid which is recrystallized from acetonitrile to afford a tan powder. The powder is recrystallized from ethyl acetate to give the title compound as a tan solid (2.09 g, 29.9%) which is identified by NMR spectral analysis. EXAMPLE 47 Preparation of 5-Amino-4-bromo-6-fluoro-3-methyl-1, 2- benzisothiazole To a solution of 5-amino-6-fluoro-3-methyl-l, 2- benzisothiazole (0.600 g, 0.00329 mol) in 1,2- dichloroethane is added N-bromosuccinimide (0.586 g, 0.00329 mol) followed by 1, 1 ' -azobis (cyclohexanecarbo- nitrile) (0.0200 g) . The mixture is stirred two hours at 70 °C, additional N-bromosuccinimide (0.240 g, 0.00135 mol) is added, and the mixture is stirred 40 minutes at 70°C. The mixture is then cooled to room temperature, filtered and concentrated in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound (0.870 g, 100%) which is identified by NMR spectral analysis.

Claims: WHAT IS CLAIMED IS: 1. A process for the preparation of a 6- (per- fluoroalkyl) uracil compound having the structural formula I (I) wherein n is an integer of 1, 2, 3, 4, 5 or 6; Y is hydrogen or Ci-Cgalkyl; and Q is a C- L -Cgalkyl group or an optionally substituted phenyl, benzyl, heteroaryl or methyleneheteroaryl group, which process comprises (a) reacting a carbamate compound having the structural formula II (ID wherein Z and Z x are each independently C- L -Cgalkyl or benzyl optionally substituted on the phenyl ring with any combination of from one to three halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl groups; and n and Y are as described above, with an amine compound having the structural formula III QNH 2 ( I I I ) wherein Q is as described above, in the presence of a base, to form the 6- (perfluoroalkyl) uracil compound of formula I wherein Y is hydrogen or C- L -Cgalkyl; and (b) optionally alkylating the formula I compound wherein Y is hydrogen to form the formula I compound wherein Y is C 1 -C 4 alkyl. 2. A process according to claim 1 wherein the double bond in the formula II compound is predominately in the (Z) - configuration. 3. A process according to claim 1 wherein the base is selected from the group consisting of a tri (Ci-Cgalkyl) - amine, a heterocyclic tertiary amine and an alkali metal C- L -Cgalkoxide. 4. A process according to claim 3 wherein the base is selected from the group consisting of 1, 8-diazabicyclo- [5.4.0] undec-7-ene and 1, 5-diazabicyclo [4.3.0] on-5-ene. 5. A process according to claim 1 wherein the carbamate compound is reacted with the amine compound in the presence of a solvent . 6. A process according to claim 5 wherein the solvent is selected from the group consisting of a carboxylic acid amide, a dialkyl sulfoxide, an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon, an alcohol, a ketone, an ether, a nitrile and water and mixtures thereof . 7. A process according to claim 1 wherein the carbamate compound is reacted with the amine compound and the base at a temperature of about 20°C to 150°C. 8. A process according to claim 1 wherein step (b) comprises reacting the formula I compound wherein Y is hydrogen with an alkyl halide having the structural formula IV or a dialkylsulfate ester having the structural formula V II XY or YOSOY ( IV) II 0 (V) wherein X is chlorine, bromine or iodine, and Y is C- L -Cgalkyl, in the presence of a base. 9. A process according to claim 1 wherein n is 1; Y is hydrogen or C 1 -C 4 alkyl; G is CH 2 or a bond; G x is CX 5 or N; G 2 is CX 4 or N; X α is hydrogen, halogen or a C 1 -C 6 alkyl group optionally substituted with one epoxy group, X 2 is hydrogen, halogen NRR 1; C0 2 R 2 , C(0)R 3 , OR 4 , S0 2 R s , S0 2 NR 6 R 7 , C(R 8 ) (OR 9 ) 2 , C (R 10 ) =NOR xl , C (R 12 ) =C (R 13 ) - C ( OR 14 ) =NOR 15 , CH 2 0 - NC0 2 R 16 , 1 , 3 -dioxolane optionally substituted with one Ci - Cgalkoxy group or one or two C 1 -C 4 alkyl groups , 1, 3-dioxolinone optionally substituted with one Ci-Cgalkoxy group or one or two C 1 -C 4 alkyl groups , or C 1 -C 4 alkyl optionally substituted with one C0 2 R 2 group and one halogen atom, and X 3 is hydrogen, halogen, C 1 -C 4 haloalkyl, C0 2 R 17 , cyano, C x -C 4 haloalkoxy, OR 18 or C 1 -C 4 alkyl, or when X 1 and X 2 are taken together with the atoms to which they are attached, they may form a five- or six- membered ring wherein X-X 2 or X 2 X X is represented by: -OC(R 20 ) (R 21 )0-, -CH 2 S(0) p N(R 22 )-, -SC(R 23 )=N-, -CH=CH- CH(R 11 )0-, -OC(0)N-, -SC(R 24 )=N-, -ON (R 25 ) C (O) - , -OC(C0 2 R 26 )=C(R 27 )-, -NC(R 28 )=C(SR 29 ) -, -CH=C (CO 2 R 30 ) 0- , -CH 2 CH(R 31 )0- or -OC (R 32 ) (R 33 ) C (O) - , or when X 2 and X 3 are taken together with the atoms to which they are attached, they may form a five- or six- membered ring wherein X 2 X 3 or X 3 X 2 is represented by: -NC(R 34 )=NC(S)-, -N(R 35 )N=C(R 36 )-, -N (R 37 ) C (R 38 ) =N- , -N(R 38 )C(0)CH 2 0-, -N(R 39 )C(0)CH=CH-, -S-N=C (R 40 ) - , -0-N=C(R 41 )-, -N=N-N(R 42 ) -, -C (R 43 ) (R 44 ) C (O) N (R 45 ) - or -N(R 46 )C(0)C(R 47 ) (R 48 )-; X 4 is hydrogen, halogen or 0R 19 ; X 5 is hydrogen or halogen; R, R S6 , R 64 , R S9 , R 70 , R 77 and R 91 are each independently hydrogen, S0 2 R 49 , C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, C 3 -Cgalkynyl, phenyl or benzyl; R x is hydrogen, SO 2 R S0 , C(0)R 51 , amino or C x -C 4 alkyl optionally substituted with C0 2 R 52 or C(0)R 53 ; ^■2' ^-16' ^i7' ^-26' ^30' ^-68' ^-75' ^76' ^82 snd R 88 are each independently hydrogen, C j -C β haloalkyl, C 3 -C 8 alkenyl, C 3 -C 6 alkynyl, phenyl, benzyl, furfuryl, pyridyl, thienyl , optionally substituted with C0 2 R 54 , morpholine or C(0)R 55 , or an alkali metal, an alkaline earth metal, ammonium or organic ammonium cation; R 3 , R β6 , R β7 , R 81 , R 8S and R 89 are each independently hydrogen, Ci-Cgalkyl, C 3 -C 6 alkenyl, C 3 -C 3 alkynyl, NR S6 R E7 , phenyl or benzyl ; R 4 , R 18 , R 19 and R 65 are each independently hydrogen, Ci-Cgalkyl, C 3 -C 6 alkenyl, C 3 -Cgalkynyl, C 1 -C 4 haloalkyl , C(0)R S8 , C(S)R 59 or benzyl; R 5 and R 72 are each independently C 1 -C 6 alkyl, C j -Cghaloalkyl, NR so K- s i' imidazole or indazole; • ^ • 6 ' '^ ■ 11 ' ■ ^ ■ 12 ' *r- ' ^15 ' ^20 ' \-l ' *^22 ' 25 ' ^28 ' *^29 ' ^31 ' ^32 / 33 ' 35 / R 45 / R 46 , R 63 and R 80 are each independently hydrogen or C 1 -C 4 alkyl; R 7 is hydrogen, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, benzyl, or C 1 -C 4 alkyl optionally substituted with cyano or C(0)R 62 ; R 8 and R 27 are each independently hydrogen, C 1 -C 4 alkyl or C- L -Calkoxy; R 9 and R 90 are each independently C- L -Cgalkyl; R 10 is hydrogen, phenyl or benzyl; R 13 , R 24 and R 36 are each independently hydrogen, C 1 -C 6 alkyl or halogen; R 23 is hydrogen or NR S3 Rg 4 ; R 34 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; R 37 is hydrogen, C 1 -C 4 alkyl or C 2 -C 8 alkoxyalkyl; R 38 and R 39 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C ε alkenyl or C 3 -C 6 alkynyl; R 40 , R 41 and R 42 are each independently hydrogen, halogen, cyano, 0R 6S , C(0)R 66 , C(S)R 67 , C0 2 R 68 , C(=NOR 69 ), a Ci-Cgalkyl, C 3 -C 7 cycloalkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl group, wherein each group is optionally substituted with any combination of one to six halogen atoms, one to three 0^-0^- alkoxy groups, one or two groups, one or two NR 70 R 71 groups, one or two S(0) q R 72 groups, one or two cyano groups, one or two C 3 -C 7 cycloalkyl groups, one OS0 2 R 73 group, one or two C(0)R 74 groups, one or two C0 2 R 75 groups, one or two C(0)SR 76 groups, one or two C(0)NR 77 R 78 groups, one to three OR 79 groups, one or two P (0) (OR 80 ) 2 groups, one 1, 3-dioxolane optionally substituted with one to three C 1 -C 4 alkyl groups, or one 1,3-dioxane optionally substituted with one to three C 1 -C 4 alkyl groups, or phenyl or benzyl optionally substituted with any combination of one to three halogen atoms, one to three groups, one to three C- L -Cgalkoxy groups, one C 3 -C 7 cycloalkyl group, one C x - C 4 haloalkyl group, one C 1 -C 4 alkylthio group, one cyano group, one nitro group, one C(0)R 81 group, one C0 2 R 82 group, one OR 83 group, one SR 84 group, one C- L -Cgalkoxymethyl group, one hydroxymethyl group, one C 3 -C 8 alkenyloxymethyl group, or one Cj- C jj haloalkoxymethyl group ,- R 43/ R 44 / R 47 and R 48 are each independently hydrogen, C 1 -C 4 alkyl, C^-^haloalkyl, C 3 -C 6 alkenyl , C 3 -C 6 alkynyl or C 3 -C 7 cycloalkyl, or R 43 and R 44 or R 47 and R 48 may be taken together with the atom to which they are attached to form a C 3 -C 7 cycloalkyl group; R 49 , R E0 and R 86 are each independently NR 93 R 94 , C 1 -C 4 haloakyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or benzyl; "51 ' "52' "53' "54' "55' "57' "58' "59' "60' "61 ' "62' "71' "73' "7 ' R 78 , R 87 and R 92 are each independently hydrogen, C- L -Cgalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, phenyl or benzyl; R 79 , R 83 and R 84 are each independently hydrogen, C(0)R 85 , S0 2 R 86 , Ci-Cghaloalkyl, C 2 -C e alkenyl, C 5 -C 8 cycloalkenyl, C 2 -Cgalkynyl, phenyl, benzyl, or C 1 -C 10 alkyl optionally substituted with one hydroxyl, benzyloxy, 0C(0)R 87 , C0 2 R 88 , C(0)R 89 , C(OR 90 ) 2 , C(0)NR 91 R 92 or cyano group; R 93 and R 94 are each independently hydrogen, C 1 -C 4 haloalkyl, C 2 -C 3 alkenyl, C 3 -C 8 cycloalkyl, Ci-C e alkyl optionally substituted with one or two C 1 -C 4 alkoxy groups or one cyanoalkyl group, or benzyl or phenyl optionally substituted with any combination of one to three halogen atoms, one to three C 1 -C 4 alkyl groups, one to three C 1 -C 4 haloalkyl groups, one to three C 1 -C 4 alkoxy groups, one to three C 1 -C 4 haloalkoxy groups, one cyano group or one nitro group, and when R 93 and R 94 are taken together with the atom to which they are attached, they form a 5- to 12-membered monocyclic or fused bicyclic, heterocyclic ring optionally substituted with one or more groups independently selected from halogen, cyano, nitro, amino, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and C 1 -C 4 haloalkylsulfonyl groups; p and q are each independently 0, 1 or 2; and Z and Z x are each independently C 1 -C 4 alkyl. 10. A process according to claim 9 wherein Y is hydrogen or methyl; X is hydrogen, fluorine or C 1 -C 3 alkyl optionally substituted with one epoxy group; X 2 is hydrogen, halogen NRR 1 C0 2 R 2 , C(0)R 3 , OR 4 , S0 2 R 5 , S0 2 NR 6 R 7 , C(R 8 ) (OR 9 ) 2 , C (R 10 ) =NOR xl , C (R 12 ) =C (R 13 ) - C (OR 14 ) =NOR 15 , CH 2 0-NC0 2 R 16 , 1, 3-dioxolane optionally substituted with one C- L -Cgalkoxy group or one or two C 1 -C 4 alkyl groups, 1, 3-dioxolinone optionally substituted with one C- L -Cgalkoxy group or one or two C 1 -C 4 alkyl groups , or C 1 -C 4 alkyl optionally substituted with one C0 2 R 2 group and one halogen atom, and X 3 is hydrogen, halogen, C 1 -C 4 haloalkyl, C0 2 R 17 , cyano, C 1 -C 4 haloalkoxy, OR 18 or C 1 -C 4 alkyl, or when X x and X 2 are taken together with the atoms to which they are attached, they may form a five- or six- membered ring wherein X X X 2 or X 2 X 2 is represented by: -OC(R 20 ) (R 21 )0-, -CH 2 S(0) p N(R 22 )-, -SC(R 23 )=N-, -CH=CH-CH(R 11 )0-, -OC(0)N-, -SC(R 24 )=N-, -ON (R 2S ) C (0) - , -0C(C0 2 R 26 )=CH-, -NC(R 28 )=C(SR 29 ) -, -CH=C (CO 2 R 30 ) O- , -CH 2 CH(R 31 )0- or -OC (R 32 ) (R 33 ) C (0) - , or when X 2 and X 3 are taken together with the atoms to which they are attached, they may form a five- or six- membered ring wherein X 2 X 3 or X 3 X 2 is represented by: -NC(R 34 )=NC(S)-, -N(R 35 )N=C(R 36 )-, -N (R 37 ) C (R 38 ) =N- , -N(R 38 )C(0)CH 2 0-, -N(R 39 )C(0)CH=CH-, -S-N=C (R 40 ) - , -0-N=C(R 41 )-, -N=N-N(R 42 )-, -C (R 43 ) (R 44 ) C (O) N (R 45 ) - or -N(R 46 )C(0)C(R 47 ) (R 48 )-; X 4 is hydrogen, halogen or 0R 19 ; X 5 is hydrogen or halogen; R, R 84 , R 69 and R 77 are each independently hydrogen, S0 2 R 49 or C 1 -C 4 alkyl; R x is hydrogen, SO 2 R S0 , C(0)R 51 , amino or C 1 -C 4 alkyl optionally substituted with C0 2 R S2 or C(0)R 53 ; independently hydrogen, C 3 -C 6 alkenyl or C 1 -C 4 alkyl optionally substituted with C0 2 R 54 , morpholine or C (0) R 55 ; R 3 , R 66 , R S7 , R 85 and R 89 are each independently hydrogen, C 1 -C 4 alkyl or NR 5ε R 57 ; R 4 , R 18 and R 19 are each independently hydrogen, C 1 -C 4 alkyl , C (0) R 58 , C 3 -C 4 alkenyl or C 3 -C 4 alkynyl ; R S6 is S0 2 R 49 ; R 57 is hydrogen or C x -C 4 alkyl ; R 5 and R 72 are each independently NR 60 R eι or indazole ; "6 ' "ll ' "12 ' "14 ' "15 ' "20 ' "21 ' "22 ' "25 ' "28 ' "29 ' "31 ' "32 ' "33 ' R 35 ' R 5 ' R 46 ano ^ R βo are eac independently hydrogen or methyl ; R 7 is C 1 -C 4 alkyl optionally substituted with cyano or C(0)R 62 ; R 8 is hydrogen or C 1 -C 4 alkoxy; R 9 and R 90 are each independently C 1 -C 4 alkyl; R 10 is hydrogen or C 1 -C 3 alkyl; R 13 , R 24 and R 36 are each independently hydrogen or chlorine ; R 23 is NR 63 R 64 ; R 34 is C 1 -C 3 haloalkyl; R 37 is C 2 -C 4 alkoxyalkyl; R 38 and R 39 are each independently C^-C- j haloalkyl, C x -C 3 alkyl or propargyl; R 40 , R 41 and R 42 are each independently hydrogen, C(0)R 66 , C(S)R 67 , C0 2 R S8 , C(=NOR 69 ) , C 1 -C 3 alkyl optionally substituted with any combination of one or two halogen atoms, one or two C 1 -C 3 alkoxy groups, one or two C 1 -C 3 haloalkoxy groups, one S0 2 R 72 group, one or two cyano groups, one C 3 -C 5 cycloalkyl group, one OS0 2 R 73 group, one C(0)R 74 group, one C0 2 R 75 group, one C(0)SR 76 group, one C(0)NR 77 R 78 group, one to two OR 79 groups, one P (O) (OR 80 ) 2 group, one 1,3- dioxolane group or one 1,3 -dioxane group, or phenyl optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR 83 group; R 43 , R 44 , R 47 and R 48 are each independently hydrogen or methyl, or R 43 and R 44 or R 47 and R 48 may be taken together with the atom to which they are attached to form a cyclopropyl group; R 49 , R 50 and R 86 are each independently C 1 -C 4 alkyl or NR 93 R 94 ; "51' "52' "53' "54' "55 ' "58' "60' "61' "62' "73' "74' ^78 a ^l R 87 are each independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 halo- alkyl ; R 79 and R 83 are each independently hydrogen , C (0) R 8S , S0 2 R 86 , C 1 -C 4 haloalkyl , C 3 - C 4 alkenyl or C 1 -C 3 alkyl substituted with one OC (0) R; 87 ' C0 2 R 88 , C(0)R 89 , C(OR 90 ) 2 or cyano group, R 93 and R 94 are each independently hydrogen or C 1 -C 8 alkyl ; p is 0 , 1 or 2 ; and Z and Z τ are each independently methyl or ethyl . 11. A process according to claim 1 for the preparation of a 6- (trifluoromethyl) uracil compound having the structural formula VI (VI ) wherein Y is hydrogen or methyl ; X 5 is hydrogen or halogen; R 40 is hydrogen, C(0)Rg 6 , C(S)R 67 , C0 2 R 68 , C 1 -C 3 alkyl optionally substituted with any combination of one or two halogen atoms, one or two C 1 -C 3 alkoxy groups, one or two C- L -Cjhaloalkoxy groups, one S0 2 R 72 group, one or two cyano groups, one C 3 -C 5 cycloalkyl group, one OS0 2 R 73 group, one or two OR 79 groups, one P(O) (OR 80 ) 2 group, one 1, 3-dioxolane group or one 1,3-dioxane group, or phenyl optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR 83 group; R 6β' R 67' R 85 an( R 89 are each independently hydrogen, C 1 -C 4 alkyl or NR 56 R : 57' R 56 is S0 2 R 49 ; R S7 is hydrogen or C 1 -C 4 alkyl; R 49 and R 86 are each independently C 1 -C 4 alkyl or NR 93 R 94 ; R 93 and R 94 are each independently hydrogen or R 68 and R 88 are each independently hydrogen, C 3 -C 6 alkenyl or C 1 -C 4 alkyl optionally substituted with C0 2 R 54 , morpholine or C(0)R 55 ; R 54' R 55' R 6c R ei' R 73 and R 87 are eac independently hydrogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; R 72 is NR 60 R 61 or indazole; R 79 and R 83 are each independently hydrogen C(0)R 85 , S0 2 R 86 , C 1 -C 4 haloalkyl, C 3 -C 4 alkenyl or C 1 -C 3 alkyl substituted with one OC(0)R 87 , C0 2 R 88 , C(0)R 89 , C(OR 90 ) 2 or cyano group; R 80 is hydrogen or methyl; and R 90 is C 1 -C 4 alkyl.

Inventors: KAMESWARAN VENKATARAMAN, KAMESWARAN, VENKATARAMAN
Applicants: AMERICAN CYANAMID CO, AMERICAN CYANAMID COMPANY
Application year: 2000
Main classification: C07D239
IPC codes: C07B61, C07D239, C07D261, C07D275, C07D417