A Domino Ring-Closure Followed by Retro-Diels-Alder Reaction for the Preparation of Pyrimido[2,1-a]isoindole Enantiomers

A simple method was developed to prepare pyrimido[2,1‐a]isoindole derivatives by using di‐endo‐ and di‐exo‐ethyl 3‐aminobicyclo[2.2.1]hept‐5‐ene‐2‐carboxylate enantiomers as chiral sources. The method is based on a domino ring‐closure reaction of norbornene 2‐aminohydroxamic acid followed by microwave‐induced retro‐Diels–Alder reaction. In the case of enantiomeric starting substances, the chirality is transferred from norbornene derivatives to pyrimido[2,1‐a]isoindoles. The configurations of the synthesized compounds were determined by 1D and 2D NMR spectroscopy [based on 2D NOE cross‐peaks and 3JH,H coupling constants] and X‐ray crystallography. Racemic and enantiomeric pentacyclic isoindoloquinazoline derivatives were prepared by a domino ring‐closure reaction starting from β‐amino hydroxamic acids. A microwave‐induced retro‐Diels–Alder reaction of these derivatives yielded racemic and enantiopure dihydropyrimido[2,1‐a]isoindoles