Theoretical Investigation on Ni-Catalyzed C(sp³)–F Activation and Ring Contraction of Tetrahydropyrans: Exploration of an S_N2 Pathway

Abstract

DFT calculations were conducted to elucidate the mechanistic details of a recently reported cross-electrophile coupling (i.e., XEC) reaction, in which a stable C(sp 3 )−F bond was successfully cleaved and a ring contraction from six-membered tetrahydropyran to three-membered cyclopropane was realized. Our theoretical investigation highlights the critical role that the Grignard reagents play. Despite being a reducing agent, the RMgX also helps to promote the C(sp 3 )−O cleavage while breaking the tetrahydropyran ring and to activate the C(sp 3 )−F bond to furnish the final recyclization. The cleavage of the C(sp 3 )−F bond follows an S N 2-type reaction, so that a chirality inversion of the carbon can be ensured. Regarding the details of the cross-coupling between two electrophiles, the pathway involving radicals is not possible for this system. According to our calculations, this reaction in fact follows an unconventional Tsuji−Trost reaction, which means that, rather than being attacked by a nucleophile, the terminal carbon of the allyl group performs a nucleophilic attack by itself. More specifically, it is realized by a methyl transfer from the RMgX to the Ni atom (i.e., methylation on the Ni atom), which is almost barrierless. In addition, the recyclization leading to the formation of cyclopropane is followed by another methyl migration, which affords a NiMe 2 species. The NiMe 2 species then undergoes a reductive elimination to regenerate the Ni(0) catalyst with a release of ethane. Meanwhile, the reductive elimination, rather than the recyclization process as proposed, is found to be the rate-determining step with an effective free energy barrier of only 69.8 kJ/mol, which ensures the reaction to proceed smoothly even at room temperature.

A Unified Explanation for Chemoselectivity and Stereospecificity of Ni-Catalyzed Kumada and Cross-Electrophile Coupling Reactions of Benzylic Ethers: A Combined Computational and Experimental Study

“…In contrast, XECs of closely related benzylic ethers proceed with retention at the benzylic center (Scheme b) and provide only XEC products, with no competitive Kumada cross-coupling observed. To reach a unified explanation for substrate-dependent chemoselectivity and stereospecificity, we undertook a combined computational and experimental mechanistic study . The increased understanding of the mechanistic underpinnings of selectivity in nickel-catalyzed Kumada and XEC reactions will provide a useful guide for future design of stereoselective transformations involving Ni-catalyzed C­(sp 3 )–O bond activation …”

Cross‐ and Multi‐Coupling Reactions Using Monofluoroalkanes

“…[88] Later, another group elucidated the reaction mechanism using theoretical calculations (Scheme 48). [89] ), the allyl group on neutral Ni complex 149 rather than the methyl reacts exclusively. It is also interesting that the bond cleavage and formation processes to construct cyclopropan rings (147 to 150) proceed through stereo inversion, consisting of stereochemical outcomes using an enantio-enriched substrate.…”

“…Later, another group elucidated the reaction mechanism using theoretical calculations (Scheme 48). [89] The reaction is triggered by oxidative cleavage of the allylic C−O bond with the aid of a Lewis acidic Mg atom ( 147 to 148 ). The methyl group transfer from MeMgX to Ni forms neutral π‐allyl Ni species 149 , and MeMgX coordinates to the F atom ( 148 to 149 ).…”

Nickel-Catalyzed Cross-Electrophile Coupling of the Difluoromethyl Group for Fluorinated Cyclopropane Synthesis

“…For example, generation of 6 from the corresponding ether or sulfonamide provides similar yield and diastereoselectivity, and cyclopropanes 16 and 17 could be prepared from the corresponding sulfonamides. Based on experimental and computational studies of related nickel-catalyzed XEC reactions, 24,30 Scheme 6 shows a plausible catalytic cycle. After binding to the arene, the nickel catalyst first undergoes oxidative addition with the benzylic ether to generate benzylnickel species 22.…”