Synthesis of Bridged Azacycles and Propellanes via Nitrene/Alkyne Cascades

Abstract

A nitrene/alkyne cascade reaction terminating in C–H bond insertion to form functionalized bridged azacycles from carbonazidates is presented. Due to an initial Huisgen cyclization, all carbonazidates reacted with the alkyne in an exo mode in contrast to the use of sulfamate esters, which react predominately in an endo mode. Substrates with different ring sizes as well as different aryl and heteroaryl groups were also explored. Variation of the nitrene tether showed that 7-membered rings were the maximum ring size to be formed by nitrene attack on the alkyne. Examples incorporating stereocenters on the carbonazidate’s tether induced diasteroselectivity in the formation of the bridged ring and two new stereocenters. Additionally, propellanes containing aminals, hemiaminals, and thioaminals formed from the bridged azacycles in the same reaction via an acid-promoted rearrangement.

Recent Advances in Construction of Polycyclic Natural Product Scaffolds via One-Pot Reactions Involving Alkyne Annulation

“…By tuning the linker in the substrates, diverse bridged, fused, spiro, or even caged products with at least one oxygen atom in the rings can be obtained. Very recently, they (Wang and May, 2020) further developed a rhodium(II)catalyzed nitrene/alkyne cascade reaction for synthesis of bridged heterocycles (Figure 13C). Although the yields are only moderate, the structural diversity is remarkable with least one oxygen atom and one nitrogen atom in the products.…”

Formation of β-Oxo-N-vinylimidates via Intermolecular Ester Incorporation in Huisgen Cyclization/Carbene Cascade Reactions

“…Thus, esters have been efficiently used as solvents in various rhodium-catalyzed carbene reactions. 14,15 To the best of our knowledge, the only intermolecular carbene reaction with esters was reported in 2018 by Davies,9 where donor/acceptor carbenes 12 reacted with esters to form tertiary alcohols 16 (Scheme 1c).…”

“…In a recent paper, we reported a Huisgen cyclization/ carbene cascade reaction to construct bridged azacycles and propellanes. 15 Investigations showed that the best solvent for that transformation was isopropyl acetate (i-PrOAc). However, an unexpected imidate 20 was found as a byproduct in 34% yield (Scheme 2).…”

“…To avoid competing C−H insertion reactions, acyclic carbonazidate 21 was used for the optimization, and the best conditions turned out to be the same as those in our previous cascade reaction. 15,16 The reaction also occurred without rhodium catalysis, but in a lower yield. In contrast, the cyclic substrate 17 gave a higher yield of imidate 20 without Rh 2 (esp) 2 (48%) than for the catalyzed reaction (34%).…”

“…Carbonazidate 21 would first undergo Huisgen cyclization to form triazole 24 as was the case in our previous studies. 15,17 After the subsequent triazole ring opening in the presence of a dirhodium catalyst, α-diazoimine 25 and then rhodium αiminocarbene 26 would be generated. Although the precise role of the rhodium catalyst is still unclear, we believe it stabilizes the carbene intermediate to avoid detrimental reactivity.…”