3.5- Disubstituted pyrazole 1-oxides

Treatment of l-benzylamino-5-methylhexan-3-one oxime 97 with copper(II) sulfate in pyridine acetonitrile yields 2,5-disubstituted pyrazole 1-oxides 98 (1994JHC281) (Scheme 28). 

Dioximes are known to generate isoxazoles and related compounds when oxidized with IBTA. However, these reactions are of limited use because of formation of side products. For example, oxidation of dioximes of /B-diketones 159 gives rise to a mixture of 3,5-disubstituted oxazoles 160 and pyrazole-di-N-oxides 161 (82MI1). In another case, oxidation of dioximes 162 affords a mixture of the isomeric dihydroisoxazolo-isoxazoles 163 and pyridazine dioxides 164 (76S837 79JOC3524 82MI1). 

Thione groups can often be eliminated by oxidation probably the sulfinic acid is the intermediate. Sometimes the sulfinic acid can be isolated (e.g., 740 741), but more often it spontaneously loses SO2. In this way, thiazoline-2-thiones give thiazoles, l,2-dithiole-3-thiones 742 are converted into 1,2-dithiolylium salts 743, l,3-dithiole-2-thiones 744 into 1,3-dithiolylium salts 745, 1,5-disubstituted imidazole-2-thiones into imidazoles <2003JHC229>, and 3-mercapto-l,2,4-triazoles into the parent triazole <2006S156>. In the pyrazole series, 746 also loses an A-methyl group to yield 747. 

The use of 1,2-disubstituted hydrazine hydrochlorides with / -keto esters seems to work well under milder conditions. The condensation of 1,2-dimethyl- or 1,2-diethylhydrazine hydrochlorides 63a,b with methyl 2-(4-fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]-3-oxopropanoate 62 required heating under reflux in ethanol to give pyrazol-3-ones 64a,b (05BMCL2285) (Scheme 15). The /i-keto ester 62 was synthesized by coupling methyl (4-fluorophenyl)acetate 60 with 2-(methylthio)pyrimi-dine-4-carboxaldehyde 61 in tetrahydrofuran with LDA at —78 °C, followed by chromium(VI) oxide oxidation. 

Recently, an efficient CuBr-catalyzed aerobic intramolecular dehydrogenative cyclization reaction of AfAf-disubstituted hydrazones to pyrazoles by a double C(sp )-H bond functionalization was developed in Ge s group (Scheme 8.67). This transformation includes C(sp )-H oxidation, cyclization, and aromatization for the formation of pyrazole products. This is the first example of an intramolecular copper-catalyzed dehydrogenative coupling reaction via an iminium ion intermediate by a C(sp )-H bond functionalization process [113]. 

---