Transforming an azaarene into the spine of fusedbicyclics via cycloaddition-induced scaffold hopping of 5-Hydroxypyrazoles

You Zhou, Shuang-Gui Lei, Baihetiguli Abudureheman, Li-Sheng Wang, Zhi-Cheng Yu, Jia-Chen Xiang () and An-Xin Wu ()
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You Zhou: Central China Normal University
Shuang-Gui Lei: Central China Normal University
Baihetiguli Abudureheman: Central China Normal University
Li-Sheng Wang: Central China Normal University
Zhi-Cheng Yu: Central China Normal University
Jia-Chen Xiang: Southeast University
An-Xin Wu: Central China Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Skeleton editing for heteroarenes, especially pyrazoles, is challenging and remains scarce because these non-strained aromatics exhibit inert reactivities, making them relatively inactive for performing a dearomatization/cleavage sequence. Here, we disclose a cycloaddition-induced scaffold hopping of 5-hydroxypyrazoles to access the pyrazolopyridopyridazin-6-one skeleton through a single-operation protocol. By converting a five-membered aza-arene into a five-unit spine of a 6/6 fused-bicyclic, this work unlocks a ring-opening reactivity of the pyrazole core that involves a formal C = N bond cleavage while retaining the highly reactive N-N bond in the resulting product. A [4 + 2] cycloaddition of a temporarily dearomatized 5-hydroxypyrrole with an in situ generated aza-1,3-diene, followed by oxidative C-N bond cleavage, constitutes the domino pathway. A library of pyrazolopyridopyridazin-6-ones, which are medicinally relevant nitrogen-atom-rich tricyclics, is obtained efficiently from readily available materials.

Date: 2024
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DOI: 10.1038/s41467-024-55312-9

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