A simple and straightforward synthesis of isoindolin-1-ones is reported. Exclusive N-cyclization of the amide functional group, an ambident nucleophile, was accomplished for the cyclization of 2-(1-alkynyl)benzamides using n-BuLi-I/ICl. The methodology works with the primary amide and affords the desired isoindolinones in yields of 38-94%. Interestingly, the isolated products exhibit a Z-stereochemistry across the C═C double bond. The reaction mechanism involving the formation of either a vinylic anion or an intimate ion pair intermediate is proposed.

Phosphazene superbase P 4 -t-Bu mediated iodoaminocyclization of 2-(1-alkynyl)benzamides is reported. The reaction works under ambient conditions and instantaneously results in the synthesis of isoindolin-1-ones in 65−97% yields, in a regio-and stereoselective manner. The exclusive formation of products with Z-geometry (across the exo CC bond) has been confirmed through X-ray crystallography. The methodology also provides an easy access to aristolactams, an important class of natural products. This has been successfully demonstrated by synthesizing two aristolactam derivatives (including Cepharanone B).

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Background: Isoindolin-1-ones are medicinally privileged heterocyclic compounds. Due to the interesting biological activities exhibited by these compounds, several synthetic and medicinal research groups have developed numerous synthetic approaches for these compounds. We have also previously reported two efficient approaches for the synthesis of the isoindolin-1-ones through iodoaminocyclization of alkynyl amides using n-BuLi and phosphazene superbases. Objective: To construct a medium size library of multisubstituted 3-methyleneisoindolin-1-ones, and to study its biological profile, specifically anti-cancer activity. Methods: Solution phase parallel synthesis has been performed for the synthesis of 3-methyleneisoindolin-1-ones library through n-BuLi-mediated iodoaminocyclization of 2-(1-Alkynyl)benzamides. The iodocyclized products were further derivatized through palladium-catalyzed Sonogashira and Suzuki Miyaura couplings and N-alkylation reactions. In silico evaluation of the physicochemical and ADMET properties was performed to check the drug likeness of the library compounds. Selected isoindolin-1-one analogues were evaluated for in vitro antiproliferative activity in various human cancer cell lines (MCF-7, A-549, and U-373 MG). Results: A library of 46 multisubstituted 3-methyleneisoindolin-1-ones has been synthesized. The iodo-isoindolin-1-ones were synthesized in 66–76% yields through n-BuLi-mediated iodoaminocyclization of 2‑(1-Alkynyl)benzamides. Further diversification afforded the diverse library members in Yields: 40–96%. Two of the library compounds exhibited GI50 values of < 10 µM in human breast cancer cell line (MCF-7). Conclusion: Isoindolin-1-one library was constructed through electrophilic cyclization. The diversification was successfully performed through various C-C and C-N bond formation reactions. The anti-proliferative activity of the library members appears to be arising from the interaction of the compounds with the protein kinase drug targets.

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