Pyrazole, 3-methyl-, chlorination

Many reagents are able to chlorinate aromatic pyrazole derivatives chlorine-water, chlorine in carbon tetrachloride, hypochlorous acid, chlorine in acetic acid (one of the best experimental procedures), hydrochloric acid and hydrogen peroxide in acetic acid, sulfuryl chloride (another useful procedure), etc. iV-Unsubstituted pyrazoles are often used as silver salts. When methyl groups are present they are sometimes chlorinated yielding CCI3 groups. Formation of dimers and trimers (308 R = C1) has also been observed. 

Bromine in chloroform and bromine in acetic acid are the reagents used most often to brominate pyrazole. When nitric acid is used as a solvent, both bromine and chlorine transform pyrazoles into pyrazolones (Scheme 24). Thus 3-methyl-l-(2,4-dinitrophe-nyOpyrazole is brominated at the 4-position (309). The product reacts with chlorine and nitric acid to give the pyrazolone (310). The same product results from the action of bromine and nitric acid on (311). The electrophilic attack of halogen at C-4 is followed by the nucleophilic attack of water at C-5 and subsequent oxidation by nitric acid. 

However, addition of bromine is accompanied by bromination of 3,5-dimethyl-pyrazolate and pyrazolate ligands at position 4, which is blocked in 4-methyl-pyrazolate. The product of electrochemical oxidation of 175 (R -- R = Me, R = Br) is 177 (R = R = Me, R = Br, X = CIO4). Chlorination proceeds similarly to bromination. 

Pyrazolo[l,2-a]pyrazoles give 3-bromo products unless the 3-position is blocked by a methyl when bromomethyl products arise (80JA4983 81JOC1666, 87JOCI673). When all of the pyrazole ring positions are filled by phenyl groups, chlorination and bromination occur in thepara-positions (74BCJ946) (see also B, 1,2). 

Pyrazolo[l,5-A benzisothiazoles 252 were prepared from 3(5)-[2 -methyl-thiophenyl]pyrazoles 251 and AT-chlorosuc-cinimide. The ring closure may involve a sequential nucleophilic heteroaromatic nitrogen displacement of a sulfonium chlorine atom followed by dealkylation of the resulting sulfonium salt to form the sulfenylimine moiety (Equation 110) <1996H(43)221>. 

In quatemized pyrazoles, 5-methyl groups are more active thus Wizinger prepared a whole series of styryl derivatives.659 The side chain chlorination of methylpyrazoles mentioned above belongs to this group of reactions.544... 

A few halogenated 3-pyrazolin-5-thiones are known (Table XVIII). These are prepared from the methyl chlorides of 3- or 4,5-dichloro-pyrazole by reaction with sodium sulfide or potassium hydrogen sulfide.795,981 Michaelis988,992 has reported that 3-pyrazolin-5-selenones form dichlorides and di- and tetrabromides when treated with chlorine or bromine. No specific structures were suggested. 

Compound 12 cyclizes with hydrazine to give a pyrazoline which can be dehydrogenated to afford pyrazole 12. Many trifluoromethylated pyrazoles are known as described in an excellent review (ref. 27). Alcohols U can be methylated using NaH/TfOMe. These methyl ethers could not be hydrolyzed to the corresponding Mosher acid. As the hydroxyl is now protected by an alkyl group, the thioamide moiety can be chlorinated to give the amide chloride 14- This unstable compound was directly cyclized with benzothiazole (Scheme 35). 

Oxadiazoles.—1,2,3-Oxadiazoles. 3-Phenylsydnone (594 R = H) is anodically chlorinated at position 4, while anodic oxidation yields mainly phenol and benzaldehyde. The foregoing sydnone reacts with tetracyanoethylene to give the ene-hydrazone (596), presumably via the cyclo-adduct (595), by loss of carbon dioxide and cleavage of the strained carbon-carbon single bond. Irradiation of diphenylsydnone (594 R = Ph) in the presence of methyl pro-piolate affords the pyrazole (597) by way of the nitrile imine PhC=N—NPh with benzonitrile, a mixture of the 1,2,3- and 1,2,4-triazoles (598) and (599), together with the 1,3,4-oxadiazolinone (600) and 7s/ -benzoyl-iV -phenylhydrazine, is formed. ATV -Dibenzoylphenylhydrazine is produced by photo-oxygenation of diphenylsydnone. 

Bridged Sulfonamides. The most convenient syntheses of 3-bridged pyrazole sulfonamides utilizes either a mercapto group or amine functionality as a handle to prepare the requisite sulfonamide. For example, one can prepare a pyrazole sulfonamide with many of the required substituents by the scheme depicted below. Condensation of methyl hydrazine with chloroacrylonitrile yields N-methyl-3-aminopyrazole 58 (12-13). The amine is protected by acylation. Chlorination at the 4 position with sulfuryl chloride, followed by deprotection provides 3-amino-4-chloropyrazole 59. The sulfonamide 60 is prepared by decomposition of the diazonium salt of 59 in SO2/CUCI followed by amination of the resulting sulfonyl chloride. 

Figure 4 shows the synthesis of 15 in which the phenyl group in the chloro carboxamide series was replaced with a t-butyl group. Compound 15 was herbicidal at 1 Ib/acre in the greenhouse. A comparison of the herbicidal activity of compounds 5, 11 and 15 showed that 11 was two times as active as 15, and four times as active as 5 (data not shown). It was determined that the analogue that best fit the structural requirements for herbicidal activity was the 5-cyano-l-(1,1-dimethylethyl)-N-methyl-lIi-pyrazole-4-carboxamide 1. However, in contrast to the phenyl series the chlorine atom of 13 was inert towards displacement by cyanide ion under a variety of conditions, apparently due to a combination of steric and electronic effects. 

The regioselectivity and reactivity of the 1,3-dipolar cycloaddition reactions of nitril-imines with acrylonitrile and methyl acrylate have been investigated. The 1,3-dipolar cycloaddition reactions of nitrilimines with isatin imines yielded spiro[indolin-3,3 -1,2,4-triazol] derivatives under classical and microwave conditions/ An extensive study of the 1,3-dipolar cycloaddition reactions of nitrilimines with a,/ -unsaturated lactones, thiolactones, and lactams has been presented. In all cases, regioisomeric mixtures were obtained with the 5-substituted pyrazole as the major cycloadduct. me5 o-Tetrakis(pentafluorophenyl)porphyrin (51) reacts with iminonitriles (52) yielding pyrazolin-fused chlorines (53) via a 1,3-dipolar cycloaddition reaction (Scheme 17). ... 

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