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

Organic & Biomolecular Chemistry Pub Date: 2022-11-02 DOI: 10.1039/D2OB01764D

Abstract

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 Br?nsted 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.

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