Switchable C2/C3 positional selectivity of thioisatins in a three-component domino reaction: combined computational and experimental studies

The nucleophile-induced domino reaction is a featured reactivity mode of thioisatin, but the C2/C3 positional selectivity towards a nucleophile has not been understood in-depth. In this work, a domino reaction of thioisatin with bromoacetophenone and tryptamine hydrochloride to produce a benzothiophene-fused eight-membered N-heterocycle was described, showing that the Bronsted acid-base form of the amine partner was crucial for the selectivity, because using tryptamine instead of tryptamine hydrochloride gave a different product. Control experiments and density functional calculations revealed that the domino reaction using tryptamine or tryptamine hydrochloride was triggered by a condensation reaction at the C2 or C3 position of thioisatin, respectively. A delicate balance between local electrophilicity and polarization effect may be responsible for the observed selectivity.

Automated summary

This study reveals the mechanism of the domino reaction of thioisatin with bromoacetophenone and tryptamine hydrochloride, and demonstrates the crucial role of the acid-base form of the amine partner in the selectivity.