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

Abstract

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.

Design and Synthesis of New 5-aryl-4-Arylethynyl-1H-1,2,3-triazoles with Valuable Photophysical and Biological Properties

“…Convenient and eco-friendly solvent-free methodology using CuI(PPh 3 ) 3 in the presence of 2,6-lutidine as catalytic system was used for the CuAAC reaction of iodobuta-1,3-diynes 6a – c with methyl 2-azidoacetate 7 [ 39 ]. Recently, the efficiency of this methodology for the synthesis of 4-ethynyl-5-iodo-1,2,3-triazoles from iodobuta-1,3-diynes was shown by us [ 35 , 40 ]. The choice of methyl 2-azidoacetate 7 as the dipolarophile caused by the potential ability of derivatization of the ester group.…”

Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

“…Taking into account that σ-acceptors attached to propargylic carbon atoms should improve both cycloalkyne stability and SPAAC reactivity, we assumed that oxacyclo­octynes fused to heterocycles (namely, benzothiophene– BT8O and isocoumarin– IC8O ) could open the way toward a new class of stable and reactive SPAAC reagents with a heterocyclo­octyne core, in which the nature of a heterocycle would serve for the fine-tuning of the reactivity. We were also encouraged by the general and rather simple synthetic route used previously for the synthesis of heterocycle-fused heteroenediynes, − which can also be applied for cycloalkynes (Scheme ).…”

“…We were very disappointed when we found that both BT8O and IC8O are extremely unstable and could not be isolated after decomplexation using a dozen common Co deprotecting reagents. In all cases of using either oxidizing decomplexation ( N -methylmorpholine- N -oxide (NMO), I 2 , cerium ammonium nitrate (CAN)) ,, or ligand exchangeable reagent: tetrabutylammonium fluoride (TBAF), ,, only complex polymeric mixtures were obtained. By treatment with other ligand exchangeable reagents (ethan-1,2-diamine (EDA), dimethylacetylene­dicarboxylate (DMAD)), the reaction did not take place at all (Table S1).…”

Synthesis and biological properties of maleimide-based macrocyclic lactone enediynes

“…32 Some members of the enediyne family are already in clinical use to treat various cancers, 33 but more general use is limited by their complicated structure, which makes them formidable targets for synthetic chemists. 34 Several attempts were made by Nicolaou, 35,36 Basak, 37,38 and Balova 39,40 et al to create simple and active synthetic analogs of natural enediynes and this kind of work is still in progress.…”