Rh(III)-Catalyzed Sequential Intermolecular [4 + 2] Cycloadditions toward Functionalized Indeno[1,2-c]isoquinolines
Mei-Yan Zhou1, Long-Kun Chen1, Huan-Huan Li1
1Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming650091, P. R. China.
Abstract:
The development of transient directing groups that are generated and erased in situ has created new opportunities for catalytic C-H functionalization. This study reported a Rh(III)-catalyzed cascade annulation of readily available amidinium salts 1 or ethyl benzimidates 2 with 2-diazoindane-1,3-diones 3, providing functionalized indeno[1,2-c]isoquinolines (IIQLs) 6 and 7. This transformation integrated C-H activation, carbene insertion, and intramolecular cyclization into a single catalytic sequence. The resulting products subsequently underwent a second Rh(III)-catalyzed [4 + 2] annulation with diarylalkynes 4 or 2-diazoketones 5, furnishing structurally complex pentacyclic frameworks 8. Mechanistic studies suggest that Lewis acid-promoted amino-imine tautomerization accompanied by double-bond migration generated a transient imine from the embedded 2-aminopyridine-type motif. This substrate-derived imine directed o-aryl C(sp2)-H activation and was subsequently erased, eliminating the need for the installation and removal of permanent directing groups as well as the use of external transient directing agents. Overall, this modular strategy enabled the efficient construction of densely fused heterocyclic architectures by combining indane-1,3-dione and isoquinoline scaffolds, providing a versatile platform for the synthesis of structurally sophisticated molecules with potential applications in medicinal chemistry.
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