Regiodivergent gold(i)-catalysed rearrangements in indole synthesis

Abstract

We report a regiodivergent gold(I)-catalysed cycloisomerisation of terminal 2-alkynyl anilines that yields either C2-o-tolylindoles via a [3,4]-sigmatropic rearrangement or C2/C3-benzylindoles via [1,2]-benzylic migration. The reaction selectivity is fully controlled by the electronic nature of the benzylic substituent. Under optimised conditions (10 mol% Au, DCE, 70 °C), substrates bearing strong electron-withdrawing groups (e.g., p-NO₂) follow the [3,4] pathway to afford C2-o-tolylindoles in up to 95% yield and with regioselectivity ratios of up to 21 : 1. Phosphine-based catalysts provided the highest efficiencies and selectivities. Density functional theory calculations show that electron-withdrawing substituents raise the activation barrier for [1,2]-benzyl migration (>14 kcal mol⁻¹), thereby favouring the [3,4] pathway. This approach enables a direct route to sterically hindered C2-o-tolylindoles, which are otherwise challenging to access through cross-coupling methods.