Does an Enol Pathway Preclude High Stereoselectivity in Iron-Catalyzed Indole C-H Functionalization via Carbene Insertion?

Balhara, R and Jindal, G (2022) Does an Enol Pathway Preclude High Stereoselectivity in Iron-Catalyzed Indole C-H Functionalization via Carbene Insertion? In: Journal of Organic Chemistry, 87 (12). pp. 7919-7933.

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Abstract

C-H functionalization of indoles via Fe carbenoids presents an attractive strategy to obtain biologically important structural motifs. However, obtaining good stereoselectivity with Fe has been a significant challenge. It is unclear whether the low selectivity is due to a radical pathway or an ionic mechanism involving metal-free species. We therefore present a density functional theory (DFT) study of indole alkylation with diazoacetates catalyzed by Fe(ClO4)TMEDA/spirobisoxazoline and myoglobin. We explore three mechanistic pathways: nucleophilic, radical, and oxocarbenium routes. The nucleophilic pathway is the most feasible with the formation of an enol species that tautomerizes to furnish the alkylated indole. While this mechanism is routinely proposed, the stereochemical model has been conspicuously absent until now. We show that the conventionally invoked enol pathway is not responsible for the low enantiomeric excess. The enol intermediate can stay coordinated to the catalyst via different binding sites placing the enol in proximity to the chiral environment and affecting the stereoselective proton transfer. Both the binding strength and the chiral environment are crucial for obtaining high selectivity. Our study provides the much needed insights for the modest-low selectivities of Fe systems and could help in expediting the discovery of an efficient catalytic system. These mechanistic underpinnings could also be applicable to other metal (Rh, Pd, Cu, etc.)-catalyzed X-H insertion reactions.

Item Type:	Journal Article
Publication:	Journal of Organic Chemistry
Publisher:	American Chemical Society
Additional Information:	The copyright for this article belongs to the American Chemical Society.
Department/Centre:	Division of Chemical Sciences > Organic Chemistry
Date Deposited:	27 Jun 2022 07:08
Last Modified:	27 Jun 2022 07:08
URI:	https://eprints.iisc.ac.in/id/eprint/73977

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