Photochemical Deracemization of Aza-1-isoindolinones: Critical Influence of Catalyst Substitution and the Nature of Its Resting State

The photochemical deracemization of aza-1-isoindolinones has been investigated. A chiral para-methoxy-substituted phenyl ketone was discovered that promotes the conversion of racemic 4-aza-1-isoindolinones into their enantiopure form upon irradiation. Products were obtained in yields of 76–96% and with an enantiomeric excess of 86–99% (23 examples). Quantum chemical calculations suggest that the catalyst acts by removing a hydrogen atom at the stereogenic center of the substrate and returning it via its N4 nitrogen atom. It was found that the intermediately formed radicals combine to form a 1:1 adduct that acts as a resting state of the catalyst. Crossover experiments and transient absorption spectroscopy provided evidence that the radical–radical recombination is reversed upon irradiation, restoring the active catalyst. Due to a notable absorption at λ = 350 nm, para-methoxy substitution seems to facilitate the cleavage, which accounts for the better performance of the substituted vs the unsubstituted phenyl ketone catalyst. When applying the catalyst to the photochemical deracemization of other aza-1-isoindolinones, it was observed that the success of the reaction depends on the stability of the intermediate formed by back hydrogen atom transfer (bHAT) from the catalyst to the substrate. Racemic 6-aza-3-benzyl-1-isoindolinone and 7-aza-3-benzyl-1-isoindolinone could be successfully employed in a photochemical deracemization, because they offer either a nitrogen atom at N6 (6-aza) or the isoindolinone oxygen atom (7-aza) to form enamine and enol intermediates upon bHAT. 5-Aza-3-benzyl-1-isoindolinone leads, in a nonpolar solvent, only to high-energy intermediates and delivers a low enantiomeric excess under standard deracemization conditions.