Synthesis and Reactivity of the 3‐Substituted Isoindolinone Framework to Assemble Highly Functionalized Related Structures

Abstract

An efficient potassium carbonate-catalyzed synthesis of 3- substituted isoindolinones through tandem aldol/cyclization reactions of active methylene compounds with 2-cyanobenzaldehyde is described. The utility of the obtained isoindolinones has been demonstrated through an exploration of the chemical space by employing a series of interesting methodologies that led to diverse, highly functionalized compounds. Among them, a surprisingly straightforward potassium carbonate-catalyzed double tandem reaction led to tricyclic hemiaminal derivatives

3-Carboxylate-Substituted Isoindolinones in K2CO3-Catalyzed Michael Reactions

“…It is worthy to note that the developed new method, in comparison to others multi-steps reported in literature for the construction of related aza-tricyclic derivatives, [18] is particularly convenient in terms of efficiency and step-economy. Moreover, the concomitant formation of the hemi-aminal functionality, which could be subjected to other transformations as reported for the analogues benzolizidines, [13][14][15] is useful for further elaboration of the tricyclic scaffold. Depending on the tested unsaturated aldehydes, the methodology allows the obtaining derivatives with two or more stereocenters diastereoselectively.…”

“…To that purpose we exploit previous findings on the oxidation of hemi-aminal group of benzoindolizidines. [13][14][15] The removing of the stereocenter at the hemi-aminal functionality by PCC oxidation, led to the interesting imide derivative 5 with an unchanged dr with respect to 3b (Scheme 2).…”

“…[6][7][8][9][10][11][12] Surprisingly, at the best of our knowledge, isoindolinones, substituted in 3-position with an electron withdrawing group, have not been attractive as nucleophiles in this fundamental reaction. As part of our ongoing studies on the synthesis of biologically relevant heterocycles, [13][14][15] we describe herein an unprecedented Michael reaction of activated isoindolinones for the construction of 3,3-disubstituted derivatives. Furthermore, among the efforts in this area [16] and in connection with our findings in the preparation of tricyclic benzoindolizidines via K 2 CO 3 -catalyzed cascade Michael/cyclization reactions, [14,15] we report a very convenient approach for the synthesis of structurally related pyrrolizidines.…”

Multicomponent Synthesis of Isoindolinone Frameworks via RhIII‐Catalysed in situ Directing Group‐Assisted Tandem Oxidative Olefination/Michael Addition

“…Literatures on existing approaches toward the synthesis of compond I include palladium‐catalysed three‐component carbonylation/amination/Michael addition process (Scheme a), hydroxyl group activation followed by nucleophilic displacement (Scheme b), base‐catalysed tandem aldol/cyclization reaction (Scheme c), intramolecular aza‐conjugate addition (Scheme d), and tandem C−H olefination/Michael addition (Scheme e) . While acknowledging these pioneering work in this field, the reported procedures a ≈ d always suffered from the use of toxic reagents, tedious synthetic routes, or harsh reaction conditions.…”

CoCl2•6H2O-Promoted Pinner-Dimroth Tandem Reaction: Facile Synthesis of 3-Substituted Isoindolinones

“…For example, Ramström et al 9 successfully assessed a base-promoted tandem reaction to access 3-substituted isoindolinones via Henry reaction, heterocyclization and rearrangement. And in a little while, Massa et al 15 described an efficient method for synthesizing 3-substituted isoindolinones through tandem aldol/cyclization reactions in the presence of potassium carbonate. Mola et al 16 discovered that the electrochemical methodology for synthesizing 3-substitued isoindolinones.…”