期刊
JOURNAL OF ORGANIC CHEMISTRY
卷 87, 期 12, 页码 7919-7933出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.2c00573
关键词
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资金
- Science and Engineering Research Board (SERB) [SRG/2019/001646]
- IISc Bangalore
C-H functionalization of indoles via Fe carbenoids is a promising method to obtain biologically important motifs, but achieving good stereoselectivity with Fe has been challenging. This study explores three mechanistic pathways and reveals that the nucleophilic pathway is the most feasible, while the commonly proposed enol pathway is not responsible for the low enantiomeric excess. The binding strength and chiral environment play crucial roles in obtaining high selectivity.
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.
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