Microwave-Assisted Branching Cascades: A Route to Diverse 3,4-Dihydroquinazolinone-Embedded Polyheterocyclic Scaffolds

Abstract

A novel metal-free microwave-assisted branching cascades strategy for the efficient synthesis of 3,4-dihydroquinazolinone-embedded polyheterocyclic scaffolds is reported. Starting from in situ generated key N-acyliminium ion precursors, 12 distinct and skeletally diverse polycyclic frameworks were accessed in a single step/pot via adjustment of the nucleophile(s) and reaction conditions. Postcascade functionalization of these compounds was also demonstrated, proving the utility of this method in accessing structurally diverse chemical entities.

Microwave-Assisted aza-Friedel–Crafts Arylation of N-Acyliminium Ions: Expedient Access to 4-Aryl 3,4-Dihydroquinazolinones

“…It is important to highlight that by changing the solvent composition the reaction can be paused at the N -acyliminium ion stage, followed by selective functionalization at the C-4 position with an external indole nucleophile, despite the presence of a pendant electron-rich aryl, thiophene, indole, or alkene nucleophile. Thus, the two-step protocol using a minimum of acetic acid can effectively suppress competing intramolecular aza -Friedel–Crafts 27 and aza -Prins cyclization 28 reactions, allowing the selective C-4 functionalization by an indole nucleophile.…”

“…As part of our ongoing research program, we recently reported a highly efficient solvent-directed diversity-oriented synthesis of skeletally diverse 3,4-dihydroquinazolinones scaffold libraries based on N -acyliminium ion chemistry under environmentally benign reaction conditions. − Our recent findings demonstrated that the intramolecular cyclization of aryl/heteroaryl tethered nucleophiles with N -acyliminium ions leads to the formation of 3,4-dihydroquinazolinone-embedded polyheterocycles (Scheme ). With the aim of developing an expedient approach to 4-aryl/heteroaryl 3,4-dihydroquinazolinones, we were encouraged to investigate the intermolecular functionalization of N -acyliminium ions ( I ) with indoles and arenes to produce 4-aryl 3,4-dihydroquinazolinone scaffold libraries based on a cascade imine/cyclization/ aza -Friedel–Crafts reaction sequence.…”

Catalytic C3 aza-alkylation of indoles

“…Here, we are going to disclose only few representative cases. Acetic acid was exploited by Odell et al 17 to synthesise a wide library of 3,4-dihydroquinazolinone-embedded polyheterocyclic scaffolds, reacting o-formyl carbamates with various amines. The reaction mechanism was based on the formation of a cyclic N-acyliminium ion, upon treatment of the carbamate with AcOH and microwaves.…”

Synthesis of substituted 3,4-dihydroquinazolinones via a metal free Leuckart–Wallach type reaction

“…26 This is a simple, highly attractive approach for accessing novel and densely substituted DHQ analogues, based on an array of different chemistries (Scheme 1). [27][28][29][30][31] During the course of our investigations on the reactivity of Nacyliminium ions (I), we observed the formation of an unknown side-product (4a) when formic acid was used as a solvent, in an aza-Henry based cyclization cascade, in lieu of acetic acid (Scheme 1). Subsequent characterization studies revealed that this compound retained the DHQ core but lacked the expected C4-substituent.…”