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  • We wanted to investigate the influence of substituents on th

    2024-06-07

    We wanted to investigate the influence of substituents on the pyrazole ring on the activity, but only a few substituted pyrazole-3-carboxylic acids/esters were commercially available in useful amounts at a reasonable price, for example, 4- and 5-nitro-pyrazole-3-carboxylic acid. The preparation of 4- and 5-alkyl substituted pyrazole-3-carboxanilides are described in the preceding Letter in this issue. Many substituted 3-methylpyrazoles are readily available, either commercially or by synthesis, and are excellent starting materials for the syntheses of pyrazole-3-carboxylic acids as KMnO expediently oxidizes the methyl group to a carboxylic CGS 21680 in acceptable yields. This approach is used, for example, for the chloro substituted pyrazoles , and (). Chlorination of 3-methylpyrazole using Cl in CCl introduces a chlorine into the 4-position of the pyrazole. A chloro substituent can also be introduced in the same starting material in the 5-position using a lithiation approach. This however requires protection/deprotection steps, and a more convenient method to synthesize 5-chloro-3-methylpyrazole is to -demethylate 5-chloro-1,3-dimethylpyrazole by heating it in pyridinium chloride. Chlorination of 5-chloropyrazole-3-carboxylic acid in the 4-position proceeds in high yield with Cl in water. 4-Bromo and 4-iodo substituted pyrazoles are readily prepared using similar tactics (not shown). As usual, the acids are converted to the corresponding carboxanilides using a SOCl mediated dimerization to a diketopiperazine followed by treatment of an appropriately substituted aniline. The synthesis of fluoro substituted pyrazoles pose a real challenge. Fluorine has been introduced in the 4-postion of pyrazole-3-carboxylic acid derivatives using F in anhydrous HF or AcOH but as we did not have the equipment to handle hazardous and corrosive F we had 4-fluoropyrazole-3-carboxylic acid ethyl ester ordered. We did not receive any details of the experimental procedure, but the small amounts of the compound we obtained consisted of a 2:1 mixture of 4-fluoropyrazole-3-carboxylic acid ethyl ester and the unsubstituted starting material, pyrazole-3-carboxylic acid ethyl ester. Hydrolysis, dimerization with SOCl and treatment with 2-chloro-4-fluoroaniline as described above, gives the desired carboxanilide (entry 11, ) in a 10:1 mixture with corresponding 4-unsubstituted compound (entry 6, ). We were also able to fluorinate pyrazole-3-carboxylic acid ethyl ester in the 4-position by using XeF/CFSOAg as the fluorinating agent, but the yield was only 7%. Attempts to synthesize 5-fluoropyrazoles all failed. Interestingly, there are several suppliers that nowadays catalog 5-fluoropyrazole-3-carboxylic acid ethyl ester, but its synthesis has to our knowledge neither been described in patents nor in the scientific literature. Routes to trifluoromethyl substituted pyrazole-3-carboxylic acid derivatives are delineated in . 4-Trifluoromethylpyrazole-3-carboxylic acid ethyl ester () was prepared by the [2,3]-dipolar cycloaddition of trimethylsilyldiazomethane to ethyl 4,4,4-trifluoro-2-butynate. The reaction is crafted after the analogous reaction between diazomethane and 4,4,4-trifluoro-2-butynoic acid, which however gives the desired compound (as the methyl ester) together with the corresponding 1-methyl- and 2-methylpyrazoles. Our synthetic route toward the 5-trifluoromethyl analogue begins with the reaction of 2-methoxypropene and trifluoroacetic anhydride. The masked 1,3-diketone formed is heated with hydrazine hydrate in ethanol to give 3-methyl-5-trifluoromethylpyrazole, which as described before, is oxidized to using KMnO. The synthesis of 4,5-bis(trifluoromethyl)pyrazoles employs the reaction between 1-aminopyridinium iodide and a / mixture of 2,3-dichloro-1,1,1,4,4,4-hexafluorobut-2-ene. The pyridine ring of the formed pyrazolo[1,5-]pyridine is oxidatively ruptured with KMnO to give . 4-Chloro-5-trifluoromethylpyrazole-3-carboxylic acid () and the two 5-difluoromethyl substituted pyrazoles and are obtained using the oxidation and chlorination approach described in . The ester is converted to the corresponding 4-fluoro-2-chlorocarboxanilide (entry 16, ) using the trimethylaluminium-mediated amidation mentioned above. For the acids to , the standard SOCl/aniline protocol was used to obtain the corresponding carboxanilides (entries 17–21, ).