The Synthetic Potential of Thiophenium Ylide Cycloadducts**

Abstract

3+2) cycloaddition reactions are undeniably one of the most robust and versatile synthetic tools in heterocyclic chemistry. The classically required 1,3-dipoles are however limited to three-atom sequences bearing stabilized formal charges in their Lewis structure. The scope of three-atom groupings possible in (3+2) cycloadditions can be greatly expanded by taking of advantage neutral three-atom components (TACs). These groupings result in zwitterionic (3+2) cycloadducts adaptable to multiple outcomes depending on structure and conditions. Herein, the intramolecular (3 +2) cycloaddition reaction between alkynyl sulfides (neutral TAC) and alkynes to provide key thiophenium ylide intermediates is first reported. These reactive species provide access to highly substituted fused thiophenes following predictable chemical sequences. Structural features on the obtained thiophenes were highly configurable by judicious choice of both alkynyl sulfide substitution and reaction conditions.

Copper and Silver Catalysis in the (3 + 2) Cycloaddition of Neutral Three-Atom Components with Terminal Alkynes

“…Only in the case of the amide linker in ( 6i ) was the yield in thiophene slightly lower (81%), a result that may be attributed to the electron-poor nature of this specific alkynyl sulfide (See Supporting Information, Section S6.1). In line with our previous experience in the use of a malonate-derived linker, ( 6j ) resulted in a much slower reaction time, but in an excellent yield.…”

“…The same thiophene derivatives could be observed for a few S -(alkyl) substituted substrates (entries 1–3). Notably, while phenyl substitution on the alkyne terminus was previously beneficial to the thermally promoted (3 + 2) cycloaddition, the reverse was observed under catalytic conditions (entry 4), with the substrate ( 9 ) remaining unaltered. These observations also countered analogous tests previously made on the terminal alkyne-ynamide scaffold ( 10 ), where no catalysis whatsoever had been observed using copper salts and various bases .…”

“…It is therefore of general interest to explore the use of other neutral three-atom components (neutral TACs) in (3 + 2) cycloadditions, providing an orthogonal set of three-atom synthons that may be used to produce 5-membered heterocycles inaccessible with classical 1,3-dipoles. Recently, X-alkynyl functional groups ( 3 ), where X is a N- or S-based molecular fragment, have been repurposed as neutral TACs that can participate in (3 + 2) cycloaddition reactions with alkynes (Figure B). − From an electronic point of view, X-alkynyl motifs ( 3 ) share a similar arrangement to propargyl–allenyl type dipoles ( 1 ). However, due to their “neutral” Lewis structure, their cycloaddition products ( 4 ) are zwitterionic.…”

“…(3 + 2) Cycloadditions involving X-alkynyl groups are, however, more demanding in energy than those involving 1,3-dipoles. For this reason, methodologies developed for these cycloaddition cascades have either used tethering groups − , or highly reactive aryne species. − …”

“…Our recent studies on the intramolecular (3 + 2) cycloaddition of alkynyl sulfides with alkynes have shown several limitations that are directly associated with this high energy demand, notably, the size of the tether between the cycloaddition partners and the substitution on the “X” heteroatom. These limitations cannot be addressed via the thermal mechanism without making scope-limiting changes in the substrate structure.…”