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Please login or sign up for a free trial to access the full content. Method 2: N-Substituted Dihydropyrazoles via 1,3-Dipolar Cycloadditions

DOI: 10.1055/sos-SD-027-00576

Kim, S.; Yoon, J.-Y.Science of Synthesis, (200427687.

When 2-(alkenyloxy)arylhydrazones 68 are heated in xylene at 150°C for 20 hours the pyrazolidines 70 are formed via intramolecular 1,3-dipolar cycloadditions of bipolar intermediates 69. The pyrazolidines 70 are usually dehydrogenated to dihydropyrazoles 71 under the reaction conditions (Scheme 16).[‌76‌] This type of reaction depends upon the electronic nature of the alkenyloxy groups of the arylhydrazone. Substrates 68 bearing alkenyloxy groups (R1=H, Me) do not undergo 1,3-dipolar cycloadditions, whereas if an electron-withdrawing group (R1=CN or COR2) is present a thermal intramolecular ene reaction occurs. In addition to these restrictions, yields of dihydropyrazoles are also variable (1065%) limiting the scope of this approach. A synthetically more useful method is to treat the hydrazones 68 with a strong acid. Under these conditions cyclization is much faster and more efficient than the thermal 1,3-dipolar cycloaddition and usually occurs at room temperature.[‌77‌,‌78‌] Such acid-promoted cyclizations are not restricted to a few aldehyde hydrazones, but also work with a variety of hydrazones derived from ketones and alkylhydrazines. Furthermore, unlike the thermal reaction, this method is effective with substrates bearing either electron-withdrawing or electron-donating alkenyloxy groups. Best results are obtained from the direct condensation of aldehydes or ketones with aryl (or alkyl) hydrazine hydrochlorides or sulfates, without the isolation of the corresponding hydrazones. In these reactions, the initially formed pyrazolidines can be isolated; thus, the aldehyde 72 when treated in turn with phenylhydrazine hydrochloride and triethylamine affords the pyrazolidine 73 (Scheme 16).[‌77‌] Such products can be further oxidized to dihydropyrazoles by heating them in xylene at reflux.

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