The invention relates to a compound of the formula I 
and the disulfide thereof and salts thereof, processes for the preparation thereof and the use thereof for the preparation of compounds having a microbicidal and plant-immunizing action, of the formula III 
in the compounds of the formulae I and III:
X is halogen,
n is 0, 1, 2 or 3;
Z is CN, COxe2x80x94A or CSxe2x80x94A,
A is hydrogen, OR1, SR2 and N(R3)R4;
R1 to R4 are hydrogen, a substituted or unsubstituted, open-chain, saturated or unsaturated hydrocarbon radical containing not more than 8 carbon atoms, a substituted or unsubstituted cyclic, saturated or unsaturated hydrocarbon radical containing not more than 10 carbon atoms, substituted or unsubstituted benzyl or phenethyl, a substituted or unsubstituted alkanoyl group containing not more than 8 carbon atoms, a substituted or unsubstituted benzoyl group or a substituted or unsubstituted heterocyclyl radical; or R3 and R4, together with the nitrogen atom to which they are bonded, are a 5- or 6-membered, substituted or unsubstituted heterocyclic radical having 1-3 heteroatoms O, S and/or N.
The compounds of the formula I have at least one basic group and can thus form acid addition salts. The se are formed, for example, with mineral acids, for example sulfuric acid, a phosphoric acid or a hydrogen halide acid, with organic carboxylic acids, for example acetic acid or oxalic, malonic, maleic, fumaric or phthalic acid, with hydroxycarboxylic acids, for example ascorbic, lactic, malic, tartaric or citric acid, or with benzoic acid, or with organic sulfonic acids, for example methane- or p-toluenesulfonic acid. On the basis of the SH group or an acid group in the substituent Z, compounds of the formula I can furthermore form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, pipesdine, pyrrolidine, a mono-, di- or ti-lower al kylamine, for example ethyl-, diethyl-, tethhyl- or dimethyl-propyl-amine, or a mono-, di- or trihydroxy-lower alkylamine, for example mono-, di- or triethanolamine. If appropriate, corresponding inner salts can furthermore be formed.
Unless defined otherwise, the general terms used above and below have the meanings given below:
Hydrocarbon radicals can be saturated or unsaturated and open-chain or cyclic, or a mixture of open-chain and cyclic, for example cyclopropyl methyl or benzyl.
Alkyl groups are straight-chain or branched, depending on the number of carbon atoms, and are, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, sec-amyl, tert-amyl, 1 -hexyl or 3-hexyl.
Unsaturated hydrocarbon radicals are alkenyl, alkynyl or alkenynyl groups with at least 3 multiple bonds, for example butadienyl, hexatrienyl, 2-penten-4-ynyl.
Alkenyl is to be understood as meaning straight-chain or branched alkenyl, for example allyl, methallyl, 1-methylvinyl or but-2-en-1-yl. Alkenyl radicals with a chain length of 3 to 4 carbon atoms are preferred.
Alkynyl can likewise be straight-chain or branched, depending on the number of carbon atoms, f or example propargyl, but-1-yn-1-yl and but-1-yn-3-yl. Propargyl is preferred.
Cyclic unsaturated hydrocarbon radicals can be aromatic, for example phenyl and naphthyl, or non-aromatic, for example cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctadienyl, or partly aromatic, for example tetrahydronaphthyl and indanyl.
Halogen or halo and Hal are fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Haloalkyl can contain identical or different halogen atoms, for example fluoromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trichloroethyl and 3,3,3-trifluoropropyl.
Alkoxy is, for example, methoxy, ethoxy, propyloxy, i-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy; preferably methoxy and ethoxy.
Haloalkoxy is, for example, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy and 2,2-difluoroethoxy.
Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Alkanoyl is either straight-chain or branched. Examples are formyl, acetyl, propionyl, butyryl, pivaloyl or octanoyl.
A heterocyclyl radical is understood as meaning 5- or 6-membered aromatic and non-aromatic rings with heteroatoms N, O and/or S. An unsubstituted or substituted benzo group can furthermore be fused onto such a heterocyclyl radical bonded to the remainder of the molecule. Examples of heterocyclyl groups are pyridyl, pyrimidinyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, triazolyl, thienyl, furanyl, pyrrolyl, morpholinyl, oxazolyl and the corresponding partly or totally hydrogenated rings. Examples of heterocyclyl groups with a fused-on benzo group are quinolyl, isoquinolyl, benzoxazolyl, quinoxalinyl, benzothiazolyl, benzimidazolyl, indolyl and indolinyl.
Compounds of the formula III having a microbicidal and plant-immunizing action and processes for the preparation thereof are known, for example, from EP-A-313,512. The processes described therein are not suitable for industrial preparation, since they comprise many reaction stages, some of which are complex, and thus overall result in an unsatisfactory yield.
There is therefore a need for a novel, industrially more advantageous synthesis for such compounds.
The compounds of the formula I according to the invention allow a novel access to the compounds of the formula III, which is shown in Equation 1. This synthesis is distinguished by easy accessibility of the percursor, use of customary reactants and good yields, even in cases where an intermediate product is not isolated. The present invention likewise relates to this synthesis.
In the formulae of Equation 1,
X, n and Z are as defined for formula I and
T is hydrogen, C1-C12alkyl, in particular C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl.
The precursors of the formula V are compounds which are obtainable industrially or can be prepared by known methods, for example by reduction of the corresponding nitro compounds. 
In detail, the reaction stages can be carried out as follows:
(1) SCN-T/for example methyl isothiocyanate/inert solvent/if appropriate in the presence of acid or base; or SCN salt.
(2) Oxidizing agent, for example SO2Cl2 or Br2 or H2SO4/bromide or Cl2.
(3) Strong aqueous base, for example potassium hydroxide solution, preferably under an inert atmosphere.
Reactions (1), (2) and (3) as such are described, for example, in
Org. Synthesis, Coll.Volume III, page 76;
J. Het. Chem. Volume 17, page 1325, (1980);
U.S. Pat. No. 5,374,737;
Ukrain.Khim.Zhur. Volume 22, 363, 1956; cited in Chem.Abstr. 22, 4358b, (1957).
(3a) Diazotization/H3PO2(Synth. Comm. Volume 10, page 167 1980)
(4) Diazotization with cyclization, for example with nitrous acid (xe2x95x90HONO) or with an inorganic or organic nitrite, for example sodium nitrite or isoamyl nitrite (for example EP A 313,512).
(4a) For example hydrazine/ethanol or basic hydrolysis, or such as 4) (Synth. Comm. Volume 10, page 167 1980).
(4b) For example Zn/acid or Fe/acid (Heterocyclic Compounds, Volume 7, page 541 et seq.); or H2/catalyst
(5) The conversion of the group COOH into a group Z where Z is as defined for formula I can be carried out by known methods, as shown in Equation 2.
Preferred compounds of the formula I are
(1) Compounds in which:
X is fluorine;
n is 0, 1, 2 or 3;
Z is CN, COxe2x80x94A or CSxe2x80x94A,
A is OR1, SR2 or N(R3)R4; and in which
R1, R2 and R3 are hydrogen, C1-C8alkyl, which is unsubstituted or substituted by 1-5 halogen atoms, C3-C6cycloalkyl, C1-C4alkoxy, phenoxy, benzyloxy C1-C4acyloxy, benzoyloxy, hydroxyl, nitro, cyano, C1-C4alkanoyl, benzoyl, carboxyl, C1-C4alkoxycarbonyl, benzyloxycarbonyl, amino, C1-C4alkylamino, C1-C4dialkylamino or heterocyclyl, C3-C6alkenyl which is unsubstituted or substituted by 1-5 halogen atoms, C3-C6alkynyl, C3-C6cycloalkyl, C1-C4alkanoyl, phenyl, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted once to three times by halogen, hydroxyl, C1-C4alkyl, halogeno-C1-C2alkyl, C1-C2alkoxy, halogeno-C1-C2alkoxy or nitro, or naphthyl, benzoyl or heterocyclyl, which are unsubstituted or substituted once to three times in an identical or different manner by halogen, C1-C2alkyl, halogenomethyl or nitro, or
R4 is hydrogen, C1-C6alkyl, phenyl or benzyl; or
R3 and R4, together with the nitrogen atom to which they are bonded, are a 5- or 6-membered ring with 1-2 heteroatoms O,S and/or N, where the rings mentioned are unsubstituted or substituted once or twice in an identical or different manner by halogen, C1-C3alkyl or C1-C2alkoxycarbonyl.
(2) Compounds in which:
X is fluorine;
n is 0 or 1;
Z is CN or COxe2x80x94A,
A is OR1, SR2 or N(R3)R4; and in which
R1 to R4 are as defined for claim 2.
(3) Compounds in which:
X is fluorine;
n is 0 or 1;
Z is CN or COxe2x80x94A,
A is OR1 or SR2; and
R1 and R2 are hydrogen, C1-C6alkyl, which is unsubstituted or substituted by 1-3 halogen atoms, C3-C6cycloalkyl or C1-C2alkoxy, C3-C4alkenyl, which is unsubstituted or substituted by 1-3 halogen atoms, C3-C4alkynyl, C3-C6cycloalkyl or phenyl, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted once or twice by halogen, hydroxyl, C1-C4alkyl, halogeno-C1-C2alkyl, C1-C2alkoxy, halogeno-C1-C2alkoxy or nitro.
(4). The compound of the formula la1 or the disulfide thereof or a salt thereof 
According to another process, compounds of the formula I can be prepared in accordance with Equation 2 via the corresponding benzodithiazolium salts VI or hydroxybenzodithiazoles VII (Houben-Weyl, E8d, Heteroarene [Heteroarenes] III, Part 4; page 2 et seq. and page 59 et seq.). 
(a) Sulfur halide, for example S2Cl2 or SCl2 (where the aniline derivative V is primarily preferably converted into the corresponding hydrochloride salt) in an inert solvent, for example acetic acid, at 0-120xc2x0 C. (J. Org. Chem. 30, 2763, J. Het. Chem 3, 518, ibid 5, 1149)
(b1) H2O/or H2O/NaOAc (0-50xc2x0 C.) (Khim. Get. Soed. (9), 1205 (1979); Synth. Comm. 23, 263)
(b2) H2O/20-100xc2x0 C. with or without a base, such as sodium bicarbonate, sodium carbonate or dilute alkali metal or alkaline earth metal hydroxide or oxide (J. Am. Chem. Soc. 68, 1594 (1946))
(c) Sulfur dihalide (for example SCl2), thionyl halide (SOCl2) xe2x88x9220 to 100xc2x0 C. (J. Het. Chem. 3, 518),
(d) S(O)L2, where L is a leaving group, such as halogen, imidazol-1xe2x80x2-yl or 1,2,4-triazol-1-yl, for example thionyldiimidazol or SOCl2, xe2x88x9230 to 100xc2x0 C., inert solvent (J. Org. Chem. 30, 2763 (1965)).
The benzodithiazolium salts VI and VII can also be further reacted in situ, without isolation and under suitable conditions (J. Chem. Soc. 1970, 2250, Houben Weyl E8d, Heteroarene [Heteroarenes] III, Part 4, page 59 et seq. (specifically page 93 et seq.)), to give benzothiadiazoles III or IIIa. 
(a) Chlorinating agent, for example SOCl2 or COCl2;
(b) Mxe2x80x94A (III), in which M is hydrogen, Li+, Na+, K+, xc2xd Mg2+ or a quaternary ammonium ion and A is as defined for formula I;
(c) Thionating agent, for example phosphorus pentasulfide or 4-methoxyphenylthio-phosphonic acid cyclodithioanhydride (xe2x80x9cLawesson""s reagentxe2x80x9d);
(d) NH3;
(e) Dehydrating agent, for example SOCl2; or COCl2;
(f) Reduction, for example with hydrogen/catalyst, or with a complex hydride, for example LiAlH2(OCH2CH2OCH3)2.
The reactions described are carried out in a manner known per se, for example in the absence or, usually, in the presence of a suitable solvent or diluent or of a mixture thereof, the reaction being carried out, as required, with cooling, at room temperature or with heating, for example in a temperature range from about xe2x88x9280xc2x0 C. up to the boiling point of the reaction medium, preferably from about xe2x88x9220xc2x0 C. to about +170xc2x0 C., and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.
Diazotizations, i.e. the reaction of a primary amine with nitrous acid or with an inorganic or organic nitrite, are advantageously carried out at xe2x88x9220xc2x0 C. to +30xc2x0 C.
Leaving groups are, for example, fluorine, chlorine, bromine, iodine, C1-C8alkylthio, such as methylthio, ethylthio or propylthio, C1-Calkanoyloxy, such as acetoxy, (halogeno)-C1-C8 alkanesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy or trifluoromethanesulfonyloxy, or substituted or unsubstituted phenylsulfonyloxy, such as benzenesulfonyloxy or p-toluenesulfonyloxy, imidazolyl, triazolyl, hydroxyl or water, preferably chlorine, bromine, iodine and p-toluenesulfonyloxy.
Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides, alkanolates, carbonates, dialkylamides or alkylsilylamides, alkylamines, alkylenediamines, non-alkylated or N-alkylated, saturated or unsaturated cycloalkylamines, basic heterocyclic compounds, ammonium hydroxides and carbocyclic amines. Examples are sodium hydroxide, hydride, amide, methanolate and carbonate, potassium tert-butanolate and carbonate, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, calcium hydride, triethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N,N-dimethylamine, N,N-diethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, N-methylmorpholine, benzyl-trimethyl-ammonium hydroxide and 1,8-diazabicyclo[5.4.0]undec-5-ene (DBU).
The reactants can be reacted with one another as such, i.e. without addition of a solvent or diluent, for example in the melt. However, the addition of an inert solvent or diluent or of a mixture thereof is usually advantageous. Examples of such solvents or diluents are: aromatic, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, such as benzene, toluene, xylene, chlorobenzene, bromobenzene, petroleum ether, hexane, cyclohexane, methylene chloride, chloroform, dichloroethane or trichloroethane; ethers, such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketones; alcohols, such as methanol, ethanol, propanol, butanol, ethylene glycol or glycerol; esters, such as ethyl acetate or butyl acetate; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoric acid triamide; nitriles, such as acetonitrile; and sulfoxides, such as dimethyl sulfoxide. Bases employed in excess, such as triethylamine, pyridine, N-methylmorpholine or N,N-diethylaniline, can also be used as so solvents or diluents. The reaction can also be carried out under phase transfer catalysis in an organic solvent, for example methylene chloride or toluene, in the presence of an aqueous basic solution, for example sodium hydroxide solution, and a phase transfer catalyst, for example tetrabutylammonium hydrogen sulfate. Typical reaction conditions can be seen from the examples.
The invention furthermore relates to the following preparation processes, in which, in the formulae mentioned under (1) to (6), the substituents are as defined in Equation 1.:
(1) A process for the preparation of a compound of the formula I or a salt thereof. 
which comprises reacting a compound of the formula 11 with a strong aqueous base to give a compound of the formula Ia or a salt thereof and further reacting this to give a compound of the formula I.
(2) A process for the preparation of a compound of the formula Ia or a salt thereof 
which comprises reacting a compound of the formula II with a strong aqueous base, in particular with potassium hydroxide solution or sodium hydroxide solution, at a temperature of 120-150xc2x0 C. under a pressure of 1-5 bar.
(3) A process for the preparation of a compound of the formula III 
which comprises
a) reacting a compound of the formula II with a strong aqueous base to give a compound of the formula Ia or a salt thereof and, if desired, either
b1) converting it into a compound of the formula III by diazotization with nitrous acid or an organic or inorganic nitrite and, if desired, converting this into a compound of the formula III; or
b2) converting it into a compound of the formula I and converting this into a compound of the formula III by diazotization with nitrous acid or an organic or inorganic nitrite.
(4) A process for the preparation of a compound of the formula IIIa 
which comprises reacting a compound of the formula II with a strong aqueous base to give a compound of the formula Ia or a salt thereof and converting this directly, without isolation, into a compound of the formula IIIa by diazotization with nitrous acid or an organic or inorganic nitrite; wherein, in particular, the first reaction stage is carried out in potassium hydroxide solution at 120-170xc2x0 C. under a pressure of 1-5 bar, and wherein the diazotization is carried out with sodium nitrite.
(5) A process for the preparation of a compound of the formula I 
which comprises hydrolysing a compound of the formula VI under neutral or basic conditions.
(6) A process for the preparation of a compound of the formula II or a salt thereof 
which comprises reacting a compound of the formula V with SCN-T or with an SCN salt in a solvent, if appropriate in the presence of an acid or base, and reacting the compound thus obtained, of the formula IV, with an oxidizing agent, for example SO2Cl2 or Br2 or H2SO4/bromide or Cl2, to give a compound of the formula II. A C1-C6alkyl isothiocyanate, in particular methyl isothiocyanate, is preferably used in the first reaction stage; suitable solvents are anhydrous carboxylic acids, for example formic acid and acetic acid; alcohols, for example ethanol and isopropanol, ketones, ethers and halogenated hydrocarbons. The two reaction steps are particularly preferably carried out in the same solvent, for example in acetic acid, and without isolation of the compound IV.
The invention furthermore relates to the novel intermediates of the formulae II, IV and VI 
or salts thereof, in which:
X is halogen,
n is 0, 1, 2 or 3;
T is hydrogen, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C6cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl;
Z is CN, COxe2x80x94A or CSxe2x80x94A,
A is hydrogen, halogen, OR1, SR2 and N(R3)R4;
R1 to R4 are hydrogen, a substituted or unsubstituted, open-chain, saturated or unsaturated hydrocarbon radical containing not more than 8 carbon atoms, a substituted or unsubstituted cyclic, saturated or unsaturated hydrocarbon radical containing not more than 10 carbon atoms, substituted or unsubstituted benzyl or phenethyl, a substituted or unsubstituted alkanoyl group containing not more than 8 carbon atoms, a substituted or unsubstituted benzoyl group or a substituted or unsubstituted heterocyclyl radical; or R3 and R4, together with the nitrogen atom to which they are bonded, are a 5- or 6-membered, substituted or unsubstituted heterocyclic radical having 1-3 heteroatoms O, S and/or N; and
Hal is halogen, CIO4 or BF4;
with the exception of compounds II and IV, in which Z is COOC2H5, n is 0 and T is hydrogen (already known from Ukrain.Khim.Zhur. Volume 22, 363,1956; cited in Chem.Abstr. 22, 4358b, 1957),
and the compound VI, in which Z is COOCH3 and n is 0 (already known from J. Chem. Soc. 1970, 2250, but without being isolated and characterized).
Preferred compounds of the formulae II, IV and VI are those in which:
X is fluorine;
n is 0 or 1;
T is hydrogen or C1-C6alkyl;
Z is CN or COxe2x80x94A,
A is OR1, SR2 or N(R3)R4; and in which
R1 to R4 are as defined; and of these, in particular those in which
A is OR, or SR2; and
R1 and R2 are hydrogen, C1-C8alkyl, which is unsubstituted or substituted by 1-3 halogen atoms, C3-C6cycloalkyl, or C1-C2alkoxy, C3-C4alkenyl, which is unsubstituted or substituted by 1-3 halogen atoms, C3-C4alkynyl, C3-C6cycloalkyl, or phenyl, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted once or twice by halogen, hydroxyl, C1-C4alkyl, halogeno-C1-C2alkyl, C1-C2alkoxy, halogeno-C1-C2alkoxy or nitro;
and of these, particularly preferably those in which
n is 0;
T is hydrogen or methyl;
Z is COxe2x80x94A,
A is OR1; and
R1 is hydrogen, C1-C6alkyl, which is unsubstituted or substituted by 1-3 halogen atoms, or C1-C2alkoxy, C3-C6cycloalkyl, or phenyl, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted once or twice by halogen, hydroxyl, C1-C4alkyl, halogeno-C1-C2alkyl, C1-C2alkoxy, halogeno-C1-C2alkoxy or nitro.
In compounds of the formula VI, Hal is preferably chlorine.
USPTO Backgrounds
USPTO Backgrounds