Patent Application
20070015805
The invention relates to a process for preparing 3-arylmethylthio- and 3-heteroarylmethylthio-4,5-dihydroisoxazoline derivatives by a one-pot process, by reacting corresponding arylmethyl- and heteroarylmethylisothiuronium salts, in the presence of an aqueous alkali metal or alkaline earth metal base, with a isoxazoline derivative to give the corresponding 3-arylmethylthio- and 3-heteroarylmethylthio-4,5-dihydroisoxazoline derivatives.
The literature discloses that isoxazoline derivatives of the formula (1) in which Ra and Rb are preferably optionally substituted alkyl radicals, Rc, Rd and Re are preferably each hydrogen, Rf is an optionally substituted aryl or heteroaryl radical and X is hydrogen, and also their halogenmethylsulfinyl and halogenmethylsulfonyl analogs for which X is halogen, have interesting herbicidal action (cf., for example, WO 2001 012613, WO 2002 062770, WO 2003 000686 and WO 2003 010165).
To prepare the abovementioned compounds, according to the processes known to date, the corresponding thioether of the formula (1) where n=0 is first prepared in each case, and is then converted further to the oxidized and halogenated derivatives.
The processes corresponding to the prior art for preparing the thioethers of the formula (1) (n=0) (for example WO 2001 012613, WO 2002 062770, WO 2003 000686 and WO 2003 010165) utilize:
The disadvantage of synthesis variant (a) is the handling of the mercaptans (3) which are for the most part toxic, malodorous and oxidation-sensitive, and the disadvantage of variant (b) is the high number of stages and the associated unsatisfactory overall yield.
It is thus an object of the invention to provide a synthesis process for the abovementioned thioethers of the formula (1) and further analogs, which avoids the abovementioned disadvantages of the processes according to (a) or (b).
The present invention thus relates to a process for preparing 3-arylmethylthio- and 3-heteroarylmethylthio-4,5-dihydroisoxazoline derivatives of the formula (I)
where
Compounds of the formula (II) can be obtained by reacting an alkylating agent of the formula R5R6CHLg where R5 and R6 are each as defined above for the formula (I) and Lg is a leaving group with thiourea.
The use of isothiuronium salts in a one-pot reaction for hydrolyzing the isothiuronium salt and converting the mercaptan formed as an intermediate in an exchange reaction is described in DE 3942946 for another reaction scheme.
In general, the reaction is illustrated by the formula scheme which follows:
The mercaptan of the formula (III) which is formed as an intermediate under the reaction conditions in which R5 and R6 are each as defined above for the formula (I)
is scavenged in situ immediately by the isoxazoline of the formula (IV). The handling of the mercaptan with the abovementioned unpleasant properties is avoided in the process according to the invention. In addition, the preparation is shortened by one stage compared to variant (a) of the prior art.
Compared to variant (b) of the prior art, the process according to the invention has a number of stages reduced by 2.
Preferred leaving groups Lg are chlorine, bromine, iodine or sulfonate groups, such as methane-, trifluoromethane-, ethane-, benzene- or toluenesulfonate.
Preferred leaving groups Lg′ are chlorine, bromine or sulfonate groups such as methane-, trifluoromethane-, ethane-, benzene- or toluenesulfonate, or methylsulfonyl, but particularly chlorine.
When the process according to the invention is employed, preference is given to compounds of the formula (I) in which R1 and R2 are each independently (C1-C4)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl, (C3-C6)-cycloalkyl, where each of the (C1-C4)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl, (C3-C6)-cycloalkyl radicals are optionally substituted by one or more radicals from the group of halogen, cyano or (C3-C6)-cycloalkyl.
When the process according to the invention is employed, particular preference is given to compounds of the formula (I) in which R1 and R2 are each independently (C1-C4)-alkyl or (C1-C4)-haloalkyl.
When the process according to the invention is employed, preference is further given to compounds of the formula (I) in which R1 and R2 are each independently methyl or ethyl which have in turn optionally each independently been mono- or polyhalogenated, preferably -chlorinated or -fluorinated.
Among the halogenated radicals, preference is given to chloromethyl and fluoromethyl, very particular preference to chloromethyl.
When the process according to the invention is employed, preference is further given to compounds of the formula (I) in which R3 and R4 are each independently hydrogen or (C1-C4)-alkyl.
When the process according to the invention is employed, particular preference is given to compounds of the formula (I) in which R3 and R4 each correspond to hydrogen.
When the process according to the invention is employed, preference is further given to compounds of the formula (I) in which R5 is an unsubstituted or substituted aryl preferably having from 6 to 10 carbon atoms or unsubstituted or substituted heteroaryl having preferably from 1 to 9 carbon atoms, preferably from 3 to 5 carbon atoms, with from 1 to 3 heteroatoms, preferably with one or two identical or different heteroatoms, from the group of N, O and S, where each of the above carbocyclic or heterocyclic radicals is optionally substituted by halogen, cyano, (C1-C3)-alkyl, (C1-C3)-haloalkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkenyl, (C1-C4)-alkoxy, (C1-C4)-haloalkoxy, (C3-C4)-alkenyloxy, (C3-C4)-alkynyloxy, (C3-C6)-cycloalkoxy, (C4-C6)-cycloalkenyloxy, (C1-C4)-alkylthio, (C1-C4)-haloalkylthio, (C3-C6)-cycloalkylthio, (C3-C4)-alkenylthio, (C4-C6)-cycloalkenylthio, (C3-C4)-alkynylthio, (C1-C4)-alkanoyl, (C2-C6)-alkenylcarbonyl, (C2-C6)-alkynylcarbonyl, arylcarbonyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-haloalkylsulfinyl or (C1-C4)-haloalkylsulfonyl.
When the process according to the invention is employed, preference is equally given to compounds of the formula (I) in which R5 is an unsubstituted or substituted aryl preferably having from 6 to 10 carbon atoms or unsubstituted or substituted heteroaryl having preferably from 3 to 5 carbon atoms with from 1 to 3 heteroatoms, preferably with one or two identical or different heteroatoms, from the group of N, O and S, where each of the above carbocyclic or heterocyclic radicals is optionally substituted by one or more identical or different radicals from the group of halogen, cyano, ethyl, methyl, haloethyl, halomethyl, halomethoxy or haloethoxy.
When the process according to the invention is employed, particular preference is given to compounds of the formula (I) in which R5 corresponds to a substituted or unsubstituted phenyl, naphthyl, thienyl, furyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, isothiazolyl, thiazolyl or oxazolyl, most preferably to a phenyl or pyrazolyl, each of which, in the case of substitution, is preferably substituted by one or more identical or different radicals from the group of halogen, cyano, ethyl, methyl, halomethoxy or halomethyl, where preference is given among the halogens to chlorine and fluorine, and in the case of halomethoxy and halomethyl very particularly to fluorine.
The isoxazolines (IV) in which Lg′ is defined as a leaving group, for example halogen, SO2Me, SOMe or similar, used as starting materials in the process according to the invention, are familiar to those skilled in the art and are described, inter alia, in:
The preparation of isothiuronium salts from the corresponding alkylating agents and thiourea is effected by literature processes, advantageously by reacting a corresponding alkylating agent of the formula R5R6CHLg where R5,R6 and Lg are each as specified above with a equimolar amount of thiourea in an inert solvent such as lower alcohols, for example methanol, ethanol or isopropanol; hydrocarbons, for example benzene or toluene; halogenated hydrocarbons, for example dichloromethane or chloroform; or ether derivatives, for example methyl tert-butyl ether, tetrahydrofuran or dioxane, at temperatures between 0° and 150° C., preferably from 20° to 100° C.
The compounds of isothiuronium salts of the formula (II) obtained in many cases by crystallization, generally without further purification steps, are reacted in the process according to the invention with equimolar amounts of the compounds of the formula (IV) under phase transfer conditions-with vigorous stirring.
Preference is given here to working in a biphasic system, in which case, as well as an aqueous, strongly basic alkali metal or alkaline earth metal hydroxide solution, preferably sodium or potassium hydroxide, with at least two equivalents of the base, the organic phase is an inert solvent such as tetrahydrofuran, diethyl ether, acetonitrile, pentane, hexane, benzene, toluene, xylene, chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, nitrobenzene or mixtures of these solvents.
It is also possible to use the more valuable reactant of the formula (II) or of the formula (IV) in each case in a slight deficiency.
Suitable phase transfer catalysts are quaternary ammonium or phosphonium salts, and also crown ethers, cryptands or polyethylene glycols. Examples of such catalysts can be found, for example, in W. P. Weber, G. W. Gokel; Phase Transfer Catalysis in Organic Synthesis, Springer-Verlag, Berlin 1977 or E. V. Dehmlow, S. S. Dehmlow, Phase Transfer Catalysis, Second Ed. Verlag Chemie, Weinheim 1983.
The reaction of the isothiuronium salts (II) with the isoxazolines (IV) is effected within a temperature range of from −10° to 150° C. under the conditions of a phase transfer-catalyzed reaction.
The reactants and the catalyst are preferably stirred vigorously under protective gas atmosphere at temperatures of from 20° to 100° C.
The compounds obtained can, if required, be oxidized and/or halogenated by reactions known to those skilled in the art.
The synthesis examples which follow illustrate the process according to the invention. Percentages are based on the weight.
2.0 g (14 mmol) of 3-chloro-5-ethyl-5-methyl-4,5-dihydroisoxazole (preparation according to WO 2001 012613) and 3.84 g (14 mmol) of 2,6-difluorobenzylisothiuronium bromide (prepared by reacting equimolar amounts of 2,6-difluorobenzyl bromide and thiourea in ethanol) were stirred vigorously under argon at room temperature with 1.22 g (4 mmol) of tetra-n-butylammonium bromide in a mixture of 100 ml of toluene and 28 g of 50% sodium hydroxide solution for 6 hours. After dilution with water, the organic phase was dried and concentrated. For purification, the residue was chromatographed on silica gel (4:1 ethyl acetate/heptane).
1.98 g (51.2% of theory) of product were obtained as a colorless oil. 1H NMR (300 MHz, CCCl3): (CDCl3): 2.80 (AB, 2H, isoxazoline CH2); 4.36 (s, 2H, CH2S)
0.81 g (3 mmol) of tetra-n-butylammonium bromide, 1.20 g (9 mmol) of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole (preparation according to WO 2001 012613) and 2.98 g (9 mmol) of 2-trifluoromethoxybenzylisothiuronium bromide (prepared by heating equimolar amounts of thiourea and 2-trifluoromethoxybenzyl bromide in ethanol) were added under argon to a mixture of 50 ml of toluene and 21 g of 50% aqueous sodium hydroxide solution. The mixture was stirred vigorously at room temperature for 6 hours. After dilution with water, the toluene phase was removed, the water phase was once again extracted by stirring with toluene and the combined organic phases were dried and concentrated. For purification, the crude product was chromatographed on silica gel (4:1 heptane/ethyl acetate).
1.68 g of product (58% of theory) were obtained as a colorless oil.
NMR (300 MHz, CDCl3): 1.21 (s, 6H, 2CH3); 2.78 (s, 2H, isoxazoline CH2); 4.24 (s, 2H, SCH2); 7.20-7.35 (m, 3H, phenyl H); 7.56 (dd, 1H, phenyl H)
4.05 g (13 mmol) of tetra-n-butylammonium bromide, 13.67 g (35 mmol) of [5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl imidothiocarbamate hydrobromide (WO 2004 013106) were added under an argon atmosphere to a mixture of 74.000 g of 50% aqueous sodium hydroxide solution and 100 ml of toluene. A solution of 6.000 g (45 mmol) of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole in a little toluene was added dropwise thereto at room temperature with vigorous stirring. The batch was stirred at room temperature for a further two hours and diluted with water. The mixture was extracted three times by stirring with ethyl acetate and the combined organic phases were dried and concentrated. For purification, the crude product was chromatographed on silica gel (3:3 heptane/ethyl acetate).
8.28 g (64.9% of theory) of product were obtained as a colorless oil. NMR (400 MHz, CDCl3): 1.41 (s, 6H, 2CH3); 2.78 (s, 2H, isoxazoline CH2); 3.82 (s, 3H, NCH3); 4.18 (s, 2H, SCH2); 6.73 (tr, 1H, OCF2H)
The compounds described in Table A below are obtained according to or analogously to the above-described Synthesis Examples A to C.
In the tables:
Me = methyl
Et = ethyl
Ph = phenyl
The above examples were all prepared according to the claimed process.
| Number | Date | Country | Kind |
|---|---|---|---|
| 102005031583.6 | Jul 2005 | DE | national |
