Theoretical Investigation on the Mechanism and Selectivity of Catalyst-Free Annulation of Ynediones and (Iso)quinoline N-Oxides

Abstract

The mechanism is investigated for tandem annulation of ynedione and (iso)quinoline N-oxide without catalyst using M06-2X functional. The [3 + 2] cycloaddition generates active isoxazolo[3,2-a]isoquinoline in stage 1, which undergoes ring-opening delivering tautomerization intermediates. A series of imine-enamine and keto-enol tautomerism takes place in stage 2. Four competitive paths exist in stage 3. The pure N-nucleophilic addition and one concerted path involving asynchronous hydrogen transfer generate pyrrolo[2,1-a]isoquinoline and pyrrolo[1,2-a]quinoline. The by-product (isoquinolin-1-yl)-2,5-diphenylfuran is difficult to obtain owing to the unavailability of starting intermediate of O-nucleophilic addition. The high regioselectivity is controlled both by thermodynamics and kinetics in stage 3. The energy barriers of most steps are decreased in THF solution verifying an advantageous solvation effect. The competitive N-and O-nucleophilic additions are supported by Multiwfn analysis on Frontier Molecular Orbital and Mayer bond order of vital transition states.