Synthetic Strategies and Cascade Reactions of 2‐Cyanobenzophenones for the Access to Diverse 3,3‐Disubstituted Isoindolinones and 3‐Aryl‐3‐Hydroxyisoindolinones

Abstract

Herein we report new methodologies for the synthesis of the challenging ketones 2‐cyanobenzophenones, based on Suzuki‐Miyaura type cross‐coupling reactions and very mild oxidation of 2‐benzylbenzonitriles. The investigation of the reactivity of the obtained ketones highlighted a very good electrophilicity in the presence of mild carbon‐ and hetero‐nucleophiles, allowing the synthesis of 3,3‐disubstituted isoindolin‐1‐ones. All the developed methodologies are highly efficient and tolerate combinations of functional groups present on both the aromatic rings.

Methyl 2-(1-methyl-3-oxoisoindolin-1-yl)acetate

“…If, on one hand, the synthesis of 3-unsubstituted and 3-mono substituted isoindolinones is widely explored and many protocols are available [1,2] reports about the synthesis of 3,3-disubstituted derivatives are relatively few because the construction of a quaternary carbon is generally more challenging [3,4]. In our recent works, we have developed a convenient access to 3,3-disubstituted isoindolinones by cascade reactions of 2-acylbenzonitriles with several nucleophiles [5,6]. In particular, the investigation of the reactivity between 2-acetylbenzonitrile and dimethyl malonate led to a very convenient synthesis of the new compound 1, dimethyl 2-(1-methyl-3-oxoisoindolin-1-yl)malonate [5], which can be of high interest for further transformations.…”

Palladium-Catalyzed Cross-Coupling of Cyanohydrins with Aryl Bromides: Construction of Biaryl Ketones

“…In contrast to some methods that focus on simple monosubstituted aryl halides, we elected to examine more challenging polysubstituted aryl bromides. For instance, the ortho-substituted aryl bromides with a cyano or fluoro tolerate electron-rich and electron-poor substituents at the 3-, 4-and 5-positions (entries [16][17][18][19][20][21][22][23][24]. Hence, incorporating various alkyl, alkoxy and halogenated groups illustrates the degree of generality for the polysubstituted aryl bromide component.…”

Asymmetric Synthesis of Isoxazol-5-ones and Isoxazolidin-5-ones

“…On the basis of previous work in which the strategy of trapping unstable intermediates allowed the isolation and transformation of challenging aldol adducts 67 or useful heterocycles, [68][69][70]…”