Pyrazoles electron-withdrawing substituents

Table 36 summarizes the known annular tautomerism data for azoles. The tautomeric preferences of substituted pyrazoles and imidazoles can be rationalized in terms of the differential substituent effect on the acidity of the two NFI groups in the conjugate acid, e.g. in (138 EWS = electron-withdrawing substituent) the 2-NFI is more acidic than 1-NFI and hence for the neutral form the 3-substituted pyrazole is the more stable. 

Compounds of this type with an electron-withdrawing substituent at C-a can be easily prepared by condensation of 2-(benzotriazol-l-yl)acetophenone 869 with aldehydes. Exclusively (E) isomers of a,(l-unsaturated ketones 870 are formed. Treatment with hydrazines converts derivatives 870 into pyrazolines 871. Elimination of benzotriazole from 871 in the presence of mild bases furnishes pyrazoles 872. When in these reactions hydroxylamine is used instead of hydrazines, the corresponding isoxazoles are obtained (Scheme 141) <2001JOC6787>. 

Pyrazoles 14, having R2, and sometimes also R1, as electron-withdrawing substituents, act as dienophiles at the C=C double bond. Thus with cyclopentadiene high yields of mixed endo (180) and exo (181)... 

Alkynes add nitrile oxides and diazoalkanes to give isoxazoles (60) and pyrazoles (61), respectively, in 1,3-dipolar cycloadditions. If an alkene is used instead of an alkyne the non-aromatic analogues (62 Z = NH, O) result (94AHC(60)26l) yields are best when the alkene contains an electron-withdrawing substituent. 

Replacement of a halogen atom in the 5-position of a pyrazole by nucleophiles is facilitated by the presence of an electron-withdrawing substituent, such as the phenylazo group, in the 4-position, where the halogen may be replaced by amino, alkylamino, dialkylamino, arylamino, sulfhydryl, and other such groups.664-660... 

Dealkylation of N-substituted pyrazoles is difficult to accomplish and has not been studied specially. Debenzylation can be brought about by the usual methods of reduction,4B4,70B 716,717 or by oxidation when the pyrazole ring is stabilized by the presence of an electron-withdrawing substituent. 

The iV-acyl group is easily removed in weakly acidic or basic media, especially from those 1 -acylpyrazoles with electron-withdrawing substituents. The kinetics of hydrolysis and aminolysis of variously substituted acylpyrazoles was studied in great detail by Hiittel,102 using ultraviolet spectroscopy. Rate constants were found for both reactions, and an attempt was made to apply Hammett s equation to substituted pyrazoles. 

The functionality needed for cyclization may be incorporated in the ketone, as exemplified in one entry of Table 7.3. Intramolecular participation was also provided by arylhydrazones derived from ethyl acetoacetate, with aryls having electron-withdrawing substituents when heated with HTI and a tertiary amine, they were transformed to ethyl l-aryl-4-hydroxy-pyrazole-3-carboxylates [37] ... 

Oxygen-containing rings can be opened by amines frequently this is followed by reclosure of the intermediate to form a new heterocycle. Thus isoxazoles containing electron-withdrawing substituents give pyrazoles with hydrazine, e.g. (183 Z = O) - (183 Z = NH), and... 

For the reversible addition of a proton, the position of equilibrium depends on the p/faH of the heterocycle, and this in turn is influenced by the substituents present on the ring electron-releasing groups enhance the basicity and electron-withdrawing substituents reduce the basic strength. The p/faH of simple pyridines is of the order of 5, while those for 1,2- and 1,3-azoles depend on the character of the other heteroatom pyrazole and imidazole, with two nitrogen atoms, have values of 2.5 and 7.1, respectively. 

The A-amination of pyrazoles with hydroxylamine <9-sulphonic acid in aqueous media at controlled pH allows the preparation of compounds with electron-withdrawing substituents. ... 

The attempted oxidation of pyrazole derivatives with electron-withdrawing substituents (R = Me R R = COOCH3 R = CHO Scheme 91) failed (2001UP4). For the same reason the oxidation of the triple bond in 4-chloro-5-(2-chloro-5-nitrophenylethynyl)-1,3-dimethyl-1/f-pyrazole was also unsuccessful. 

The tide compounds are obtained in moderate to good yields. While the 3- and 5-biphenyl-substituted derivatives 24 and 25 can be synthesized by applying the same reaction conditions, the synthesis of 1-biphenylsubsti-tuted pyrazoles 26 requires a different set of conditions, most notably dichloromethane as solvent instead of tetrahydrofuran (THF). The 3-biphe-nylsubstituted pyrazoles 25 are generally obtained in the h hest overall yields. In terms of the appHed boronic acid 22, electron-donating, electroneutral, and electron-withdrawing substituents are accepted. 

Electron-donating and electron-withdrawing substituents on the aryl iodide 6 are equally well tolerated, while heteroaryl iodides are generally not tolerated except for 1-thienyl iodide. In comparison to the weU-desciibed alkynone approach towards pyrazoles with acid chlorides as starting materials, this sequence allows the introduction of unprotected phenol groups. 

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