Ynamides as Three-Atom Components in Cycloadditions: An Unexplored Chemical Reaction Space

Abstract

While 1,3-dipolar cycloadditions have appeared to be a fertile area for research, as attested by the numerous synthetic transformations and resulting applications that have been developed during the past 60 years, the use of neutral three-atom components (TACs) in (3+2) cycloadditions remains comparatively sparse. Neutral TACs, however, have great synthetic potential given that their reaction with a π system can produce zwitterionic cycloadducts that may be manipulated for further chemistry. We report herein that ynamides, a class of carbon π systems that has seen wide interest over the last two decades, can be used as neutral TACs in thermally induced intramolecular (3+2) cycloaddition reactions with alkynes to yield a variety of functionalized pyrroles. The transformation is proposed to occur in a stepwise manner via the intermediacy of a pyrrolium ylide, from which the electron-withdrawing group on the nitrogen atom undergoes an intramolecular 1,2-shift to produce the neutral pyrrole. This work demonstrates a yet unexplored facet of ynamide reactivity with great potential in heterocyclic chemistry.

Enantioselective Rh(II)-Catalyzed Desymmetric Cycloisomerization of Diynes: Constructing Furan-Fused Dihydropiperidines with an Alkyne-Substituted Aza-Quaternary Stereocenter

“…Although [3+2] cycloaddition reactions of alkynes with 1,3-dipolars are common, the use of neutral three-atom components (TACs) remains comparatively sparse . In our work, the alkynal was unprecedentedly used as a neutral three-atom component to engage [3+2] cycloaddition with a π-system, affording the fused furans.…”

The Synthetic Potential of Thiophenium Ylide Cycloadducts

“…Overall, this (3+2) process was tolerant of all types of alkynyl groups that were accessed, and presents an alkyne scope noticeably larger than that found in the case of ynamides. 20 A variety of substrates possessing a three, four and fivemembered linker were synthesized, many promoting the yne-alkynyl sulfide (3+2) cycloaddition (Table 2, Part B). Exchanging the model ether linker by a sulfonamide or a malonate group led to moderate to good yields of the corresponding thiophenes 10u and 10w.…”

“…Recently, our group reported that ynamides 7 -being N-C-C neutral TACs -react intramolecularly with alkynes 1 to produce a wide variety of polycyclic fused pyrroles via the postulated intermediacy of a (3+2) pyrrolium ylide cycloadduct 6. 20 It was observed that all ynamides accessed -derived from carbamates, urea, sulfonamide and sulfamides -cleanly displayed a 1,2-migration of the electron withdrawing group (EWG) in this process to produce 2-EWG substituted pyrroles (Figure 1, Path A). This reliable reactivity was used as a basis to experimentally and theoretically investigate the nature of the unprecedented (3+2) cycloaddition step.…”

“…24,25 To date, the (3+2) cycloaddition between alkynyl sulfides 8 and alkynes 1 has not been addressed. Other than the recent work on ynamides, 20,21 the literature on heteroatomsubstituted alkynes as TACs is limited to the pyrolysis of neat compounds 17 or the use of highly reactive benzynes as 2-atom cycloaddition partners, [18][19] which both impose great limits on functional group tolerance and structural diversity. With the prediction that alkynyl sulfides and alkynes may produce thiophenium ylides upon heating, ynetethered alkynyl sulfides presented a great platform for studying a variety of S-substituted thiophenium ylides.…”

The Synthetic Potential of Thiophenium Ylide Cycloadducts**

“…In the case of neutral N-alkynyl TACs, the formation of the key pyrrolium ylide of interest can be considered to some extent as tied to the EWG 1,2-migratory outcome, a process that was calculated to have a low energy barrier (< 5 kcal mol À 1 ). [20] In order to study the synthetic potential of the elusive heteroarylium ylides 6 in further details, a neutral TAC easy to access, and more stable under diverse structural modifications would be required. Although various heteroatomsubstituted alkynes have been synthesized in the past, alkynyl sulfides 8 were found to best fit these criteria.…”