Substituted Pyrazoles

The need for pyrazoles substituted with the trifluoroacetyl group led to the reaction of ethoxyvinyl ether with trifluoroacetic anhydride, yielding 4-ethoxy-l,l,l-trifluoro-3-buten-2-one (38) this further reacted with aldehyde / fZ-butyUiydrazones, and after cyclization at room temperature under mildly acidic conditions the pyrazoles were obtained in satisfactory yields (eq. 7). Further treatment with H2SO4 removed the tert-huty group, thus providing an opportunity for further derivatization at N. ... 

C3N2 N N — — — Pyrazole substituted pyrazoles A - and A -pyrazolines pyrazolinones pyrazolidines pyrazolidinones... 

Simple HMO calculations (68JCS(B)725) satisfactorily account for the UV spectra of a great number of pyrazoles substituted by methyl and phenyl groups. The spectra of pyrazolium and indazolium salts (free bases in IN HCl) have been compared with calculated transitions (Pariser-Parr-Pople method) (74MI40403). 

Pyrazolo[3,4-d]pyridazines (555) can be prepared readily from hydrazines and pyrazoles substituted in positions 4 and 5 with an acyl and an ester group, or with two ester groups. 4,5-Pyrazolinediones have been used as starting materials for the synthesis of the quinoxaline derivatives (548) (see above) and of pyrazolo[3,4-e][l,2,4]triazines (556)... 

Because the reactive 4-position of pyrazole is substituted in indazole (benzo[b]pyrazole), substitution by electrophiles occurs by default in the 3-position initially, and then in the 5- and 7-positions of the fused benzene ring (ortho and para to the N-l). Anionic indazoles always halogenate at C-3 (84MI22). 

Scheme 6.149 Typical products obtained from the 139-catalyzed asymmetric Michael addition of protected hydroxyl amines to a,P-unsaturated 2,4-dimethyl pyrazole substituted substrates.

Scheme 6.150 Proposed mechanistic picture for (S)-favored enantioselective Michael addition of O-benzylhydroxylamine to 2,4-dimethyl pyrazole substituted a,P-unsaturated substrates in the presence of hydrogen-bonding thiourea catalyst 139.

Pyrazoles substituted with an aminovinyl or isocyanatovinyl group are useful precursors. For example, the Vilsmeier formylation product 148 on treatment with ammonium chloride, hydroxylamine, or ammonium acetate affords the aldehyde 149, oxime 150, or the 7,7 -dimer 151, respectively.142... 

Pyrazoles substituted in the 1-, 3-, or 5-position with a p-tolyl group are converted to the corresponding stilbenyl derivatives, with benzalan-ilines in the presence of potassium hydroxide, only in very low yield (Table X). Thus, 1,3-di-(p-tolyI)-5-phenylpyrazole (128) reacts with benzalaniline to give only a 2% yield of the l,3-di(stilben-4-yl)-5-phenylpyrazole (129).11... 

The hydrogen atom of the imino group of pyrazoles is sufficiently active to take part in Mannich reactions. Thus, pyrazoles unsubstituted on nitrogen, with formaldehyde and secondary amines, react smoothly to give high yields of dialkylaminomethyl derivatives (64) which are acid labile.653-656 Pyrazoles substituted on nitrogen give... 

The photolytic decomposition of pyrazoles substituted by the organosulfanyl group (for the preparation, see ref 12) in the presence of electrophilic alkenes gives cyclopropane derivative 5 in good yields (see also Houben-Weyl, Vol. E19b, p 1689). With nucleophilic alkenes, on the other hand, a mixture of products is formed, and the yields of the cyclopropanes are low. ... 

Other structural studies by ICR include basicity of methylpyrazoles (13 compounds) <90JA1303> acid-base properties of trifluoromethylpyrazoles in the gas phase <9lJOC3942> the determination of the gas-phase proton affinities of 32 A-H and A -methyl pyrazoles and the analysis of these data by comparison with ab initio 6-3IG calculations <92JOC3938>. The gas-phase basicities of eight pyrazoles substituted only at position 4 (R = H, NO2, F, Cl, C02Et, CH3, NHj, 1-adamantyl) were measured and the experimental values discussed in two ways (i) by comparing these values with AMI calculated proton affinities and (ii) within the framework of the Taft-Topsom analysis of substituent effects <95JCS(P2)1875>. 

Only 4-substituted derivatives are found to increase the inhibition of pyrazole. Substitutions in position N-1, C-3, or C-5 abolish the inhibitory power (271,277). It has recently been shown 277) that by increasing the chain length in the 4-alkyl-substituted derivatives from methyl to pentyl, the inhibitory power increases, consistent with the presence of a hydrophobic active site pocket (Table XIII). 

Pyrazoles substituted in the 1-position are metalated with n-butyllithium in the 5-position. 5-Substituted pyrazoles can be synthesized if the 1-substituent is a removable protecting group, e.g. di-methylsulfamoyl [129] ... 

Concerning pyrazoles, substitution of a in the 4-position by an (ethylamino)methyl or an (isopropylamino)methyl group provides the ligand and the bridged dirhodium complexes with a good solubility, presumably because the ammonium function introduced does not interact with the rhodium centers as represented for the tetracarbonyl complex (2) [17]. 

Complexes with pyrazole-based ligands are a frequent subject of chemical investigations aimed at understanding the relationship between the structure and activity of the active site of metallo-proteins. The metal ion in biological systems is often coordinated to one or more imidazole groups, which are part of histidine fragments of the proteins. A thermoanalytical and structural study of several copper complexes with pyrazole substitutes has been reported [156]. 

Xu et al. [25] synthesized pyrazole-substituted derivatives bearing rhodanine-3-fatty acid moieties and analyzed their antimicrobial activities against various gram-positive as well as gram-negative bacteria. Compound (IX) bearing a rhodanine-3-pentanoic acid displayed the most potent activity with a MIC of 2 pg/mL against MRSA. 

R. Kalirajan, L. Rathore, S. Jubie, B. Gowramma, S. Gomathy, S. Sankar, Microwave assisted synthesis of some novel pyrazole substituted benzimidazoles and evaluation of their biological activities, Indian J. Chem. Sect. B SOB (2011) 1794-1799. 

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