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

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(ClO 4 )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.

Investigating the Nature of the Onium Ylide and Michael Acceptor in a Rhodium(I)-Catalyzed Multicomponent Reaction

“…The enol species is typically considered to be metal-free. However, recently we have shown the crucial role of metal-associated enol species in an Fe-catalyzed two-component reaction . For the Rh-enolate species, too, the binding is typically considered from the enolate oxygen.…”

Oxidized Bridged Carbenoids as Viable Intermediates in a Fe(III) Catalyzed C−H Insertion Reaction

“…Thus, even the water assisted pathway presents a very high activation free energy barrier. We envisaged another possibility based on our previous report of Fe(II) catalyzed indole functionalization, where the intermediate coordinates to the catalyst in a passive manner [17] . The cyclopropyl indoline intermediate, F , coordinates to the catalyst via its CN group.…”

“…We envisaged another possibility based on our previous report of Fe(II) catalyzed indole functionalization, where the intermediate coordinates to the catalyst in a passive manner. [17] The cyclopropyl indoline intermediate, F, coordinates to the catalyst via its CN group. Gratifyingly, the activation free energy barrier becomes 26.4 kcal/mol for the monocarbenoid pathway involving 4 TS(F Fe -P) 2w (Figure 10).…”

“…This will also help in developing enzymatic reactions that are currently only feasible under a reducing atmosphere. Owing to our interest in the study of Fe catalyzed carbene insertion reactions, [17] in the current work, we have undertaken a comprehensive computational study using DFT methods to understand the mechanistic underpinnings of indole alkylation catalyzed by Fe(III). The energies in the text are reported at the PCM (water) /(U)B3LYP-D3/ 6-311 + + G(d,p),SDD(Fe)//(U)B3LYP/6-31G(d,p),LANL2DZ(Fe) level of theory unless specified.…”

Synthesis and Characterization of Donor–Acceptor Iron Porphyrin Carbenes and Their Reactivities in N–H Insertion and Related Three-Component Reaction

“…Iron porphyrin-catalyzed carbene transfer reaction is one of the most powerful synthetic strategies in organic chemistry . With the extensive investigations on the excellent catalytic performance of cytochrome P450 enzymes for numerous biochemical reactions, iron porphyrin carbenes (IPCs) have been generally recognized as the reactive intermediates for a broad range of iron porphyrin-catalyzed carbene transfer reactions starting from diazo compounds, including cyclopropanation, C–H, , N–H, and O–H insertion, multicomponent reactions, and olefination of carbonyl compounds as well as many other types of transformations (Scheme a) . As a result, studies toward the structure and reactivity of IPCs have always been one of the central tasks in iron porphyrin chemistry. ,, …”