Gold-Catalyzed Cyclization of 2-Alkynylaldehyde Cyclic Acetals via Hydride Shift for the Synthesis of Indenone Derivatives

Abstract

An efficient gold-catalyzed cyclization of 2-alkynylaldehyde cyclic acetals has been developed for the synthesis of indenone derivatives. A wide variety of functionalized indenone derivatives can be obtained in good-to-excellent yields. HMBC and NOESY NMR analyses and mechanistic elucidation experiments revealed that the cyclization occurs via a 1,5-H shift. The cyclic acetal group promoted the 1,5-H shift by activating the benzylic C–H bond and preventing the migration of the alkoxy group by tethering both alkoxy groups.

Revealing Mechanism and Origin of Reactivity of Au(I)-Catalyzed Functionalized Indenone Formation of Cyclic and Acyclic Acetals of Alkynylaldehydes

“…Experimentally, when terminal alkyne was not beared a phenyl ring as shown in alkyne 1f, its indenone product was not formed. 11 Following the same protocol shown above, our interrogations referred to that this substrate can participate in 1,4-H and 1,5-H shift initiations with the 1,5-H shift being relatively faster (see TS1f and TS1f', Figure 5). On one hand, our calculations revealed that the 1,4-H shift is higher than 1,5-H shit by 1.0 kcal/mol via TS TS1f' (Figure 5 , right).…”

“…It seems that the tether impedes the migration and activates the benzylic C−H bond to promote the 1,5-H shift and deactivates the 1,5-methoxy migration. 11 Therefore, understanding this transformation is highly sound regarding the detailed description of reaction mechanism and the origin of reactivity for this catalysis. We were then interested in several questions coincide with this transformation to be studied and performed through computational approaches of DFT quantum mechanics to evaluate the feasibility of the proposed reactivity of Au(I)-catalyzed cyclization to provide an insight into the nature of cyclization if it is stepwise or concerted C-H insertion (Figure 1-c).…”

“…7,10 Recently, Yamada and co-workers have evolved a highly selective and yielding Au-catalyzed synthesis of functionalized indenone derivatives through cyclization of 2-alkynylaldehyde cyclic or tethered acetals that involves 1,5-hydride shifts promoted by the acetal group (Figure 1-a). 11 The functionalized indenones were achieved in high a yield and selectivity when the aldehyde group was protected with a tethered acetal unit. However, in the absence of tether a methoxy-migrated product was obtained (Figure 1-a).…”

Revealing the Mechanism and Origin of Reactivity of Au(I)-Catalyzed Functionalized Indenone Formation of Cyclic and Acyclic Acetals of Alkynylaldehydes

“… Furthermore, Nakamura and Yamamoto and co-workers discovered the Pt- and Pd-catalyzed cyclization of 2-alkynylbenzaldehyde dialkyl acetals to achieve carbocycles (Scheme ). Furthermore, the hydride shift methodology has also been used and well-recognized in the literature for carbocycle synthesis. , Recently, Yamada and co-workers have evolved a highly selective and yielding Au-catalyzed synthesis of functionalized indenone derivatives through cyclization of 2-alkynylaldehyde cyclic or tethered acetals that involves 1,5-hydride shifts promoted by the acetal group (Figure a) . The functionalized indenones were achieved in a high yield and selectivity when the aldehyde group was protected with a tethered acetal unit.…”

“…Importantly, the migration mechanism of an acetal unit (or methoxy group) is tolerable when the acetal group is untethered and proceeds in a similar mechanistic pathway to the 1,5-H initiated pathway (Figure b, left). It seems that the tether impedes the migration and activates the benzylic C–H bond to promote the 1,5-H shift and deactivates the 1,5-methoxy migration . Therefore, understanding this transformation is highly sound regarding the detailed description of the reaction mechanism and the origin of reactivity for this catalysis.…”