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.

本研究考察了分子内Nicholas反应（intramolecular Nicholas reaction）在制备与吲哚、1,2,3-三唑、异色满酮（isocoumarin）稠合的10元氧杂与氮杂烯二炔中的应用可行性。针对与杂环（heterocycle）稠合的非环烯二炔前体，通用合成策略包含分子间与分子内丁-1,3-二炔环化反应以生成碘乙炔基杂环（iodoethynylheterocycles），随后进行Sonogashira偶联（Sonogashira coupling）。杂环与亲核基团的性质均会影响通过Nicholas反应实现10元环合的可能性。在氧杂环体系中，成功获得了与异色满酮稠合的烯二炔。对于与吲哚稠合的氧杂烯二炔，反应并未生成10元环，而是在三氟化硼（BF3）介导下，羟基对C3位邻近的三键发生加成反应，得到二氢呋喃基取代的吲哚。对于1,2,3-三唑稠合的类似物，以对甲苯磺酰胺基（NH-Ts）作为亲核官能团时，可获得10元氮杂烯二炔；而带有羟基的底物仅能得到痕量目标10元氧杂环产物。本研究还报道了一种改进的环烯二炔钴配合物脱保护方法：以四丁基氟化铵（tetrabutylammonium fluoride）在丙酮/水混合溶剂中进行脱保护，同时考察了10元烯二炔在伯格曼环化（Bergman cyclization）反应中的反应活性。固态下，所有合成的碘乙炔基杂环均能以氧或氮原子作为卤键受体，形成卤键（halogen bond, XB）。