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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.

To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothiophene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas-type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.

The feasibility of ring-closing metathesis (RCM) as a synthetic entry to 10- and 11-membered dienediynes fused to a benzothiophene core was explored by experimental and theoretical investigations. An established sequence of iodocyclization of o-(buta-1,3-diynyl)thioanisoles followed by Sonogashira coupling to form diethynylbenzothiophenes was used to synthesize terminal benzothiophene-fused enediyne diolefins as substrates for RCM. Encountering an unexpected lack of reactivity of these substrates under standard RCM conditions, we applied DFT calculations to reveal that the underlying cause was a positive change in Gibbs free energy. The change in Gibbs free energy was also found to be positive for RCM of indole- and benzannulated terminal diolefins when affording smaller than 12-membered rings. We found that modification of the enediyne-diolefin substrate as the Co2(CO)6-alkyne complex allowed the target benzothiophene-fused 11-membered dienediyne to be obtained via RCM; the alkyne complexation strategy therefore provides one valid technique for overcoming challenges to macrocyclization of this kind.

Novel poly(arylene ethynylene)s comprising a cinnoline core were prepared in high yields via a three-step methodology. A Richter-type cyclization of 2-ethynyl- and 2-(buta-1,3-diynyl)aryltriazenes was used for cinnoline ring formation, followed by a Sonogashira coupling for the introduction of trimethylsilylethynyl moieties and a sila-Sonogashira coupling as the polycondensation technique. The fluorescence of the cinnoline-containing polymers in THF was highly sensitive to quenching by Pd2+ ions.

Examples of intramolecular cyclizations of functionalized diacetylenes are considered in the review. Cyclizations occur with the participation of one of the triple bonds that leads to ethynyl-substituted heterocycles, or of two triple bonds that is used in the synthesis of polycondensed heterocyclic systems and ensembles.

An efficient strategy for the synthesis of asymmetrically substituted enediynes fused to benzothiophene, benzofuran, and indole was developed. The proposed approach is based on the electrophilic cyclization of diacetylenes and Sonogashira coupling. Thus, iodocyclization of readily available ortho-functionalized (buta-1,3-diynyl)arenes was used as a direct way for the synthesis of 2-ethynyl-3-iodoheteroindenes. These substrates and their modified derivatives were easily converted by Sonogashira coupling with acetylenes to a variety of asymmetrically substituted acyclic enediynes fused to heterocycles. The tolerance of the developed methodology to a variety of functional groups is a great advantage in the synthesis of macrocyclic enediyne systems fused to a heterocyclic core. Synthesis of indole-fused 12-membered macrocyclic dienediyne was achieved using ring-closing metathesis as a key step.