Sealed-Tube-Assisted One-Pot Oxidative Aromatization of Dihydropyrazolo[1,5-a]pyrimidines Using Sodium Persulfate and Mg–Al Hydrotalcite

We report a sealed-tube-assisted one-pot oxidative aromatization of in situ-generated dihydropyrazolo[1,5-a]pyrimidine intermediates to afford polymethoxylated pyrazolo[1,5-a]pyrimidine derivatives using sodium persulfate in ethanol, utilizing the Mg-Al hydrotalcite (Mg-Al HT) as a solid base catalyst. Dihydropyrazolo[1,5-a]pyrimidine intermediates are firstly produced efficiently by an aza-Michael addition followed by a cyclocondensation sequence under sealed tube condition performed by Q-tube instrument and subsequently aromatized in situ utilizing sodium persulfate as a sustainable oxidant in a true one-pot fashion. Subsequent treatment of the catalyst-containing reaction mixture with sodium persulfate under sealed-tube heating afforded the corresponding aromatized products. Control experiments showed that the oxidation was enhanced under ambient-air conditions, while appreciable conversion was retained after nitrogen purging. This integrated operation is kinetically advantageous: direct addition of persulfate to the crude reaction mixture provides the target pyrazolo[1,5-a]pyrimidines in up to 91–92% isolated yield within 10 min, whereas oxidation of isolated intermediates under otherwise identical conditions requires longer reaction times. Optimized conditions utilize merely 3 mol% Na2S2O8, yielding the necessary pyrazolo[1,5-a]pyrimidines with an isolated yield of up to 91% within 10 min, demonstrating superior efficiency and environmental compatibility compared to N-bromosuccinimide and selenium dioxide. The approach accommodates various aminopyrazoles with polymethoxy chalcone, facilitating quick access to a limited collection of purine-mimetic heterocycles with possible therapeutic relevance. The methodology tolerates the recyclable Mg–Al hydrotalcite catalyst and the use of ethanol as a benign solvent, aligning the overall process with the principles of sustainable chemistry through reduced energy input, low oxidant loading, and minimized waste generation.