Electronic and Steric Effects in a Gold(I)-Catalyzed Intramolecular C(sp3)-H Bond Activation Reaction of 1-Bromoalkynes

The functional group compatibility of our recently disclosed gold(I)-catalyzed cycloisomerization of 1-bromoalkynes is studied in detail. Two main features are addressed, the minimum distances at which polar functional groups are tolerated and the influence of both electronic and steric effects on the performance of aryl ether derivatives. Moreover, robustness assessment experiments have been carried out shedding light on the factors dictating functional group tolerance. In addition, the reaction has been applied to the synthesis of a key intermediate in the total synthesis of a natural product and a heterobifunctional molecule. DFT calculations have shed light on the mechanistic features behind the observed reactivity trends. On one hand, the destabilization of the TS by the proximity of the polar group may hamper the reactivity for proximal functional groups. On the other hand, some polar functional groups are not tolerated regardless of their position due to the preferential coordination of gold to the oxygen atom over the alkyne, resulting presumably in competitive catalyst deactivation pathways.