5‑Annulation of Ketoimines: TFA-Catalyzed Construction of Isoindolinone-3-carboxylates and Development of Photophysical Properties Anirban Kayet, Sk Ajarul, Sima Paul, and Dilip K. Maiti* Department of Chemistry, University of Calcutta, University College of Science, 92, A. P. C. Road, Kolkata 700009, India * S Supporting Information ABSTRACT: Herein we have demonstrated the first report on 5-annulation of ketoimines to valuable isoindolinone-3- carboxylates. Instead of commonly used aldimine substrates, relatively less reactive ketoimines are employed for developing a TFA catalyzed organoreductive cyclization to furnish a variety of isoindolinones in excellent yield and reaction rate under mild reaction conditions. This is a metal-free event, which proceeds through a one pot ketoimine formation, hydride transfer from an organic reductant 2-(naphthalen-2-yl)-2,3-dihydrobenzo[d]thiazole, and followed by five member cyclization sequences through TFA-activation of imine and ester groups. Studies on ESI-MS kinetics, leaving group aptitude, and control experiments led us to propose the mechanistic pathway of the new ketoimine-lactamization reaction. We have shown the synthetic utility of the emerging synthons through easy transformation of isoindolinones to different synthetic analogues. We investigated photophysical properties of the small molecules for their futuristic application as a pharmaceutical and materials, and the heterocycles displayed brilliant fluorescence activity. ■ INTRODUCTION The motivation of a researcher in the synthetic chemistry field is to devise an effective strategy for a challenging reaction using uncommon synthons to desirable compounds with installation of extra functionalities and selectivities. For instance, commonly used aldimine synthons 1,2 may be replaced by ketoimines 3 to achieve the goal of reckoning extra substituents, functionalities, and/or stereogenic centers. However, ketoimines are in general difficult to synthesize, purify, and store, have E/Z isomers, are relatively unreactive in nature, and suffer from steric congestion during nucleophilic addition. 4 Contrary to the wide use of aldimines, ketoimines have found limited application as synthons, particularly in the metal-free cyclization 5 and 5- annulation. 6 In particular, aldimines are frequently used for syntheses of valuable 3-substituted isoindolinones 2 employing metal Lewis acids such as Rh(I), Cu(I), Cu(II), Zn(II), and In(III) for the lactamization and C3-alkylation or multistep reactions. It can easily be performed through a sustainable direct approach involving strongly coordinated transition state of ketoimines (TS, Scheme 1) with a Brønsted acid catalyst (R 4 CX 2 H). The isoindolinone-3-carboxylates and carboxamide analogues were found as therapeutic inhibitors of microsomal triglyceride transfer protein and apolipoprotein B secretion (i, Figure 1), 7 state-dependent blockers of voltage-gated sodium channel Na V 1.7 and medicine for pain disorder (ii), 8 function modulator for muscarin and serotonin receptors, aldose reductase inhibitor for diabetics (iii), antihyperglycemic, and anxiolytics, 9 blood pressure regulatory inhibitors of phosphatidylinositol-3-kinase, medicine for cardiac arrhythmias, inhibitors for HIV-reverse transcriptase and renin. 10 Thus, isoindolinone-3-carboxylates are emerged as attractive synthons for enantioselective Michael reaction, 11 spirolactonization, 12 hydrogenated octahydroisoin- dole core structure, 13 and large scale synthesis of pharmaceut- icals 7 of Pfizer. The widely used synthons are most frequently synthesized using the methods as described by Massa et al. and Rammah et al. through coupling of amines with hazardous α- bromohomophthalates. 11,12 The other important strategies were reported involving precursor phthalimide derivatives, NH 3 / CN - and CO 2 (via lithiation), 14 carbon monoxide fixation Received: April 25, 2018 Article pubs.acs.org/joc Cite This: J. Org. Chem. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.joc.8b01049 J. Org. Chem. XXXX, XXX, XXX-XXX Downloaded via UNIV OF WINNIPEG on July 7, 2018 at 04:56:37 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.