1 -Alkyl-5-methylpyrazoles

In the reactions of nucleophilic addition to diacetylene, monoalkylhydrazines behave in two ways (71AKZ743). In an anhydrous medium at 40-50°C, the reaction with methyl- and ethylhydrazines proceeds in such a way that a more nucleophilic disubstituted nitrogen atom attacks the terminal carbon atom of diacetylene to form l-alkyl-3-methylpyrazoles (17), the content of isomeric 1-alkyl-5-methylpyrazoles being 15% according to GLC (71AKZ743 73DIS 77AKZ332). 

We have already noted (Section 4.04.2.1.4(xi)) that alkyl groups on pyrazoles are oxidized with permanganate to carboxylic acids. Silver nitrate and ammonium persulfate transform 4-ethyl-1-methylpyrazole (436) into the ketone (437) (72JHC1373). The best yield was obtained starting with the alcohol (438) and using an acid dichromate solution as oxidizing agent. 

Boiled in a water-dioxane solution in the presence of acids, these compounds turn into l-alkyl-3-propynyl-5-methylpyrazoles (Scheme 25). 

In aqueous solutions, the prevailing process is the primary attack of the unsubstituted nitrogen atom of alkylhydrazines at the terminal carbon atom of diacetylene with predominant formation of l-alkyl-5-methylpyrazoles (18) (73DIS). The content of isomeric l-alkyl-3-methylpyrazoles is less than 10% (GLC). In the authors opinion, this different direction of the attack at diacetylene in aqueous media is related to the hydration of alkylhydrazines and the formation of ammonium base RN" H2(0H) NH2, in which the primary amino group becomes the major nucleophilic center. 

The other possible isomer, 1,4-dimethylpyrazole (and its other N-alkyl and -aryl analogues), reacted with chlorine in dichloroethane at 25-35°C to produce 5-chloro derivatives in around 70% yields (90EUP366329). 5-Aryl-3-methylpyrazoles were chlorinated by NCS at C-4 (86JHC459), as were a range of pyrazoles by chloroperoxidase in the presence of hydrogen peroxide and potassium chloride at pH 2.9. Yields of 68-83% make this latter process an improvement over some traditional chemical methods (87JHC1313). 

Deprotonation can occur at the -GH of pyrazole A-alkyl groups for example 1-methylpyrazole with -BuLi. Such proton loss is facilitated in cationic azido rings, and the ylides so formed sometimes undergo rearrangement. Thus, quaternized 1,2-benzisoxazoles 796 lose a proton and then rearrange to 1,3-benzoxazines, e.g., 797. Quaternized derivatives of benzofuroxan formed in situ undergo rearrangement to 1-hydroxybenzimidazole A-oxides 798. Reactions of this type are also known for A-alkylazolinones. 

The preparation of tebufenpyrad and tolfenpyrad (see below) are outlined in Scheme 28.3.4. The pyrazole ring is prepared from a Claisen condensation of 2-butanone with diethyl oxalate followed by treating the resulting acylpyruvate with hydrazine [45, 46]. The pyrazole ring is then alkylated with dimethyl sulfate at 50-60 °C without base to give, selectively, the l-methylpyrazole-5[Pg.893]

---