Intramolecular Nicholas Reactions in the Synthesis of Heteroenediynes Fused to Indole, Triazole, and Isocoumarin

The
applicability of an intramolecular Nicholas reaction for the
preparation of 10-membered O- and N-enediynes fused to indole, 1,2,3-triazole,
and isocoumarin was investigated. The general approach to acyclic
enediyne precursors fused to heterocycles includes inter- and intramolecular
buta-1,3-diyne cyclizations with the formation of iodoethynylheterocycles,
followed by Sonogashira coupling. The nature of both a heterocycle
and a nucleophilic group affects the possibility of a 10-membered
ring closure by the Nicholas reaction. Among oxacycles, an isocoumarin-fused
enediyne was obtained. In the case of O-enediyne annulated with indole,
instead of the formation of a 10-membered cycle, BF3-promoted
addition of an OH-group to the proximal triple bond at the C3 position
afforded dihydrofuryl-substituted indole. For 1,2,3-triazole-fused
analogues, using NH-Ts as a nucleophilic functional group allowed
obtaining 10-membered azaenediyne, while the substrate with a hydroxyl
group gave only traces of the desired 10-membered oxacycle. An improved
method for the deprotection of Co-complexes of cyclic enediynes using
tetrabutylammonium fluoride in an acetone/water mixture and the investigation
of the 10-membered enediynes’ reactivity in the Bergman cyclization
are also reported. In the solid state, all synthesized iodoethynylheterocycles
were found to be involved in halogen bond (XB) formation with either
O or N atoms as XB acceptors.