Enantioselective Alkylation of Unactivated C–O Bond: Solvent Molecule Affects Competing β-H Elimination and Reductive Elimination Dynamics

Abstract

Despite the fact that metal-catalyzed asymmetric alkylative cross-couplings have been well-established, enantioselective alkylative substitution of an unactivated C–O bond remains a challenge due to the lack of strategies to cleave the C–O bond and suppress β-H elimination as well as control stereochemistry simultaneously. Herein, the enantioselective alkylative activation of an unactivated C–O bond with β-H-containing alkylating reagents was described using a chiral nickel catalyst, and versatile axially chiral biaryls bearing alkyl moieties with different chain lengths were delivered in good yields and with high ee. Control experiments demonstrated the significant role of the solvent tetrahydrofuran to facilitate this transformation. DFT calculations revealed that the coordination of THF to Mg­(II) is pivotal for suppressing β-H elimination during reductive elimination, thus unlocking how the solvent molecule affects the competing β-H elimination and reductive elimination dynamics in transition-metal-catalyzed alkylative cross-coupling reactions.

The Ring‐Opening Reaction of Benzofuran Involving the Cleavage of C−O Bond

“…This transformation was carried out in the presence of L3 as the ligand and MgI 2 as the additive, using THF as the solvent at 45 °C (Scheme 12). [25] Control experiments revealed that the transformations were equally efficient without the presence of inorganic salts MgI 2 , ruling out its role in suppressing β‐H elimination. These control experiments highlighted the crucial role of the solvent THF in facilitating these transformations.…”

Development of Configurationally Labile Biaryl Reagents for Atropisomer Synthesis

“…The catalytically active species in the arylation is the mono‐ligated nickel, while catalytically active species in the alkylation is the bis‐ligated nickel. The same group also developed similar strategies to suppress β ‐H elimination in alkylative cross‐couplings via the unique solvent effect of tetrahydrofuran [38] . Recently, Gu, Shi, Deng, and co‐workers developed a regioselective C(sp 2 )−O bond activation method for C−N atropisomer synthesis (Scheme 8b) [39] .…”

“…The same group also developed similar strategies to suppress β-H elimination in alkylative cross-couplings via the unique solvent effect of tetrahydrofuran. [38] Recently, Gu, Shi, Deng, and co-workers developed a regioselective C(sp 2 )À O bond activation method for CÀ N atropisomer synthesis (Scheme 8b). [39] The high regioselectivity benefits from the high stability of the in situ formed (amido)ethenolate via oxidative addition.…”

Transition-metal-free synthesis of functional 2-arylphenols by an intermolecular SNAr reaction between dibenzofurans and various nucleophiles

“…12 Very recently, the Cao group developed the asymmetric version of this transformation using ring strained dibenzofurans at 25 °C to 60 °C. 13 It is worth highlighting that the above examples represent the breakthroughs within this domain. However, the ring opening of dibenzofurans and the subsequent formation of C–O, C–N, and C–P bonds are still limited.…”