Ni-Catalyzed Larock Indenone Annulation with Aliphatic- and Silyl-Substituted Alkynes Supported by Mechanistic Analysis

Abstract

A Ni-catalyzed annulation reaction to synthesize indenones is reported. The reaction provides high yields and regioselectivities when aliphatic- and silyl-substituted alkynes are employed. Both have been challenging and underutilized substrate classes. Several mechanistic observations aided in the development of this reaction, including that β-hydride elimination is turnover-limiting for ortho-halogenated aldehyde substrates and that alkyne dissociation is rate-limiting for internal aliphatic alkynes. We anticipate that these methods will be rapidly adopted due to their synthetic ease and inherent versatility. We also anticipate that the mechanistic conclusions will inform further reaction development.

Indenone Synthesis via Transition‐Metal‐Catalyzed Annulation

“…In 2022, Wilger and coworkers reported a Ni‐catalyzed indenone synthesis that used methyl ortho ‐bromobenzoate esters as aromatic precursors ( 48 , Scheme 42). [16b] Initial studies with ortho ‐bromobenzaldehyde ( 6 ) indicated that alkyne dissociation was rate‐limiting under conditions with excess alkyne. Reaction byproduct analysis and KIE studies indicated that β‐hydride elimination was turnover‐limiting with benzaldehyde derivatives.…”

“… Selected examples for Ni‐catalyzed indenone synthesis with methyl ortho ‐bromobenzoate esters and silyl‐substituted alkynes (Wilger, 2022) [16b] …”

“… Mechanism proposed for Ni‐catalyzed indenone synthesis with methyl ortho ‐bromobenzoate esters (Wilger, 2022) [16b] …”

“…Many of these advances have focused on expanding the variety of aromatic precursors that can be used for indenone synthesis. For example, salicylaldehyde triflates [16a] and ortho ‐halogenated benzoate esters [16b] both offer advantages in terms of accessibility when compared to ortho ‐halogenated benzaldehyde derivatives (Figure 22). Directed C−H activation has become a readily available and manifold platform for indenone synthesis, especially using Pd, [8] Rh, [10a,e–j,l] Co, [13a,b] Fe, [17] and Re [18] catalysts.…”

“…In the Ni‐catalyzed reaction reported by Wilger, even a secondary isopropyl substituent was insufficient to install meaningful regioselectivity (Figure 26). [16b] The only apparent exception to this limitation would be a more highly functionalized indenone reported Chatani [10c] . In this case, an unsymmetrical alkyne containing a pendant carbonyl group was employed to test whether a putative vinylrhodium intermediate would undergo competitive side reactions.…”