Ag-Catalyzed [2 + 1 + 2] Cycloaddition with Isocyanide toward Imidazo[1,5-a]isoquinolin-1-amines

Imidazo[1,5-a]isoquinolin-1-amine is a common structural motif in pharmaceuticals and a promising bioisostere of imidazo[1,2-a]pyridin-3-amine. However, most synthetic routes to this scaffold are limited by their reliance on external chemical oxidants and prefunctionalized substrates. In this article, silver-catalyzed [2 + 1 + 2] cycloaddition with isocyanide is first realized with the aid of microwave irradiation. Notably, isocyanide could serve as crucial "CN" and "C1" synthons for the first time in isocyanide chemistry. Screening of all synthesized compounds against the DU145, A549, and HCT116 cell lines revealed that the imidazo[1,5-a]phthalazin-1-amine derivative exhibits enhanced anticancer activity compared to its bioisostere, with an IC₅₀ value of 9.97 μM against HCT116. This synthetic approach not only offers an efficient bond-forming alternative for imidazo[1,5-a]isoquinolin-1-amines for medicinal chemistry, but also provides novel insights into isocyanide chemistry.