Asymmetric C(sp3)–H functionalization of unactivated alkylarenes such as toluene enabled by chiral Brønsted base catalysts

Hirata, Tsubasa; Sato, Io; Yamashita, Yasuhiro; Kobayashi, Shū

doi:10.1038/s42004-021-00459-5

Cited by 25 publications

(10 citation statements)

References 24 publications

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“…Then, we turned our attention to the fourth reaction type, a benzyl radical addition to imines. Previous examples for photocatalyzed benzylic C–H addition to imines were limited to using benzyl ethers, activated imino esters, and ethyl benzene as substrates . The catalytic combination of 7,7’-OMe-TPA (10 mol %) and 15 (5 mol %) successfully promoted the reaction between N - tert -butyl imine 16 and alkyl arenes ( 17 ) in the presence of TFA (Figure B).…”

Section: Resultsmentioning

confidence: 99%

Identification of a Self-Photosensitizing Hydrogen Atom Transfer Organocatalyst System

et al. 2022

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We developed organocatalyst systems to promote the cleavage of stable C−H bonds, such as formyl, α-hydroxy, and benzylic C−H bonds, through a hydrogen atom transfer (HAT) process without the use of exogenous photosensitizers. An electronically tuned thiophosphoric acid, 7,7'-OMe-TPA, was assembled with substrate or co-catalyst N-heteroaromatics through hydrogen bonding and π−π interactions to form electron donor−acceptor (EDA) complexes. Photoirradiation of the EDA complex induced stepwise, sequential single-electron transfer (SET) processes to generate a HAT-active thiyl radical. The first SET was from the electron-rich naphthyl group of 7,7'-OMe-TPA to the protonated Nheteroaromatics and the second proton-coupled SET (PCET) from the thiophosphoric acid moiety of 7,7'-OMe-TPA to the resulting naphthyl radical cation. Spectroscopic studies and theoretical calculations characterized the stepwise SET process mediated by short-lived intermediates. This organocatalytic HAT system was applied to four different carbon−hydrogen (C−H) functionalization reactions, hydroxyalkylation and alkylation of N-heteroaromatics, acceptorless dehydrogenation of alcohols, and benzylation of imines, with high functional group tolerance.

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Section: Resultsmentioning

confidence: 99%

Identification of a Self-Photosensitizing Hydrogen Atom Transfer Organocatalyst System

et al. 2022

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“…It has been proposed that the deprotonation is facilitated by the formation of cation−π interactions between group(I) metals and arenes. , Some recent examples from our work include the aminobenzylation of toluenes (Scheme a) and an efficient indole synthesis from 2-fluorotoluene (Scheme b), both using MN(SiMe 3 ) 2 bases with Cs + additives. Others have used stronger bases to deprotonate toluene derivatives, including mixed bases [ n -BuLi, t -BuOK, and TMP (TMP = 2,2,6,6,-tetramethylpiperidine) by O’Shea, t -BuOK and LiTMP or KCH 2 TMS and KN(SiMe 3 ) 2 by Kobayashi, KZn(N(SiMe 3 ) 2 ) 3 by Mulvey, and LDA by Guan] . For deprotonation of substituted toluenes, Schlosser’s super base ( n -BuLi/ t -BuOK) exhibits a high degree of substrate dependency.…”

Section: Introductionmentioning

confidence: 99%

Benzylic Aroylation of Toluenes Mediated by a LiN(SiMe₃)₂/Cs⁺ System

Zhang

Wang

et al. 2021

J. Org. Chem.

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Chemoselective deprotonative functionalization of benzylic C–H bonds is challenging, because the arene ring contains multiple aromatic C(sp2)–H bonds, which can be competitively deprotonated and lead to selectivity issues. Recently it was found that bimetallic [MN(SiMe3)2 M = Li, Na]/Cs+ combinations exhibit excellent benzylic selectivity. Herein, is reported the first deprotonative addition of toluenes to Weinreb amides mediated by LiN(SiMe3)2/CsF for the synthesis of a diverse array of 2-arylacetophenones. Surprisingly, simple methyl benzoates also react with toluenes under similar conditions to form 2-arylacetophenones without double addition to give tertiary alcohol products. This finding greatly increases the practicality and impact of this chemistry. Some challenging substrates with respect to benzylic deprotonations, such as fluoro and methoxy substituted toluenes, are selectively transformed to 2-aryl acetophenones. The value of benzylic deprotonation of 3-fluorotoluene is demonstrated by the synthesis of a key intermediate in the preparation of Polmacoxib.

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“…Not surprisingly, the alternative nucleophilic benzylation reaction has also received broad attention. Since the benzylic C–H without activation of an adjacent functional group is not easily deprotonated to generate the carbanion species, the methyl-substituted electron-deficient heteroarenes or arenes bearing strong electron-withdrawing groups, are commonly employed, and excess strong Brønsted bases and/or Lewis acid activation are usually necessary for the relevant nucleophilic benzylation reaction, as illustrated in Scheme a, (i) and (ii) . Lundgren disclosed a decarboxylative allylic benzylation with aryl acetic acids or esters, but the substrates having an electron-deficient (hetero)aryl group must be used [Scheme a, (iii)] .…”

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Asymmetric Formal Nucleophilic o-Cresolylation with Morita–Baylis–Hillman Carbonates of 2-Cyclohexenones via Palladium Catalysis

Xue

Zhang

et al. 2022

J. Am. Chem. Soc.

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Here we report an asymmetric formal nucleophilic o-cresolylation reaction with the Morita–Baylis–Hillman (MBH) carbonates from 2-cyclohexanones and diverse aldehydes under palladium catalysis, by in situ generation of electron-neutral and HOMO-raised η2-Pd(0)-dienone complexes via an oxidative insertion/π–σ-isomerization/β-H elimination activation sequence. The subsequent umpolung vinylogous addition to a variety of imines is realized upon Pd(0)-mediated π-Lewis base catalysis, finally furnishing o-cresolylated products followed by another cascade of a π–σ-isomerization/β-H elimination/aromatization process. Moderate to excellent diastereo- and enantioselectivity are achieved for substantial substrate assemblies by employing a newly designed bulky chiral phosphonamidite ligand, and the resultant multifunctional products can be facilely elaborated to access diverse enantioenriched architectures. In addition, the catalytic reaction pathway is finely illuminated by control experiments.

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Asymmetric C(sp3)–H functionalization of unactivated alkylarenes such as toluene enabled by chiral Brønsted base catalysts

Cited by 25 publications

References 24 publications

Identification of a Self-Photosensitizing Hydrogen Atom Transfer Organocatalyst System

Identification of a Self-Photosensitizing Hydrogen Atom Transfer Organocatalyst System

Benzylic Aroylation of Toluenes Mediated by a LiN(SiMe₃)₂/Cs⁺ System

Asymmetric Formal Nucleophilic o-Cresolylation with Morita–Baylis–Hillman Carbonates of 2-Cyclohexenones via Palladium Catalysis

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Asymmetric C(sp3)–H functionalization of unactivated alkylarenes such as toluene enabled by chiral Brønsted base catalysts

Cited by 25 publications

References 24 publications

Identification of a Self-Photosensitizing Hydrogen Atom Transfer Organocatalyst System

Identification of a Self-Photosensitizing Hydrogen Atom Transfer Organocatalyst System

Benzylic Aroylation of Toluenes Mediated by a LiN(SiMe3)2/Cs+ System

Asymmetric Formal Nucleophilic o-Cresolylation with Morita–Baylis–Hillman Carbonates of 2-Cyclohexenones via Palladium Catalysis

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Benzylic Aroylation of Toluenes Mediated by a LiN(SiMe₃)₂/Cs⁺ System