Stereospecific Indium(III)‐Catalysed Tandem Cycloisomerization of Functionalized 1,6‐enynes: Scope and Mechanistic Insights

Abstract

AbstractTandem cycloisomerization reactions of functionalized 1,6‐enynes under indium(III) catalysis are described. This atom‐economic transformation proceeds smoothly with 5‐exo‐dig regioselectivity using commercial In(III) halides and 1,6‐enynes furnished with alcohol, carboxylic acid or amine functional groups to give bicyclic structures in good yields and diastereoselectivities. The reaction with enynals involves a three–step mechanism to give an oxatricycle and a conjugated 1,3‐diene. In the absence of the internal nucleophile the enyne cycloisomerization evolves through a skeletal rearrangement or a cyclopropanation reaction after the regioselective 5‐exo‐dig cyclization. The 1,6‐enyne cycloisomerization is stereospecific and the stereoselectivity appears to be independent of the internal nucleophile. Experimental data support a common reaction mechanism involving an initial alkyne electrophilic π‐coordination of In(III) followed by Markovnikov electrophilic alkene addition and ring‐closure by nucleophilic attack. DFT studies hold up a stepwise mechanism involving the formation of a chiral non‐classical carbocation intermediate that determines the diastereoselectivity of this tandem cycloisomerization reaction.