Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers via Synergistic Pd/Cu Catalysis

Ke, Miaolin; Li, Xinzhi; Zong, Jiayi; Wang, Bowen; Zheng, Jinying; Zhang, Shujia; Chen, Jian-Ai; Chen, Fener

doi:10.1021/acs.orglett.3c04375

Org. Lett.

2024

DOI: 10.1021/acs.orglett.3c04375

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Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers via Synergistic Pd/Cu Catalysis

Miaolin Ke,

Xinzhi Li,

Jiayi Zong

et al.

Abstract: We developed an asymmetric decarboxylative allylic alkylation of vinylethylene carbonates with α-fluoro pyridinyl acetates through a synergistic palladium/copper catalysis. This protocol provides chiral allylic alcohol with carbon−fluorine quaternary stereogenic centers in good yield with good enantioselectivities and excellent regioselectivities. The utility of this approach was further demonstrated via a gram-scale experiment and derivatizations of the product.

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Cited by 4 publications

References 58 publications

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Pd‐Catalyzed Allylic Substitution Using Nucleophilic Amines: Access to Functionalized Mono‐ and Bis‐N‐Allyl Synthons

Gao,

Ghorai,

Benet‐Buchholz

et al. 2024

Adv Synth Catal

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We here report a catalytic strategy to enable the decarboxylative allylic amination of vinyl cyclic carbonates using various aliphatic and nucleophilic amines. The use of a protic medium and chelating diphosphine ligands is a main driver towards chemo‐selective allylic amine formation, thereby minimizing undesired ligand‐driven complex speciation and aminolysis of the involved substrate. This improved approach amplifies the repertoire of allylic amine synthons that can be prepared from a variety of substrate combinations.

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Pd‐Catalyzed Allylic Substitution Using Nucleophilic Amines: Access to Functionalized Mono‐ and Bis‐N‐Allyl Synthons

Gao,

Ghorai,

Benet‐Buchholz

et al. 2024

Adv Synth Catal

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Copper-Catalyzed Asymmetric Tertiary Radical Cyanation for the Synthesis of Chiral Tetrasubstituted Monofluoroacyl Nitriles

Liu,

Jiang,

Tang

et al. 2024

Org. Lett.

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The construction of chiral tetrasubstituted α-fluoro-α-cyano carbonyl compounds remains a key challenge in synthetic organic chemistry because of their popularity in multiple disciplines. In this paper, we report the copper-catalyzed asymmetric fluorinated tertiary radical cyanation reaction of cyclic α-iodo-α-fluoroindanones with TMSCN to achieve chiral nitriles with carbon−fluorine quaternary stereogenic centers. Thus, an array of optically active tetrasubstituted monofluoroacyl nitriles were synthesized with high reaction efficiency and excellent enantioselectivities (up to 91% yield, 99% ee). Moreover, mechanistic investigations, including experiments, were conducted to clarify the reaction pathway and stereochemical outcomes. D ue to the distinctive properties of fluorine, it is extensively employed in chemical modification across various fields. Fluorine incorporation can effectively modulate the pK a , lipophilicity, molecular conformation, and metabolic stability of the parent compound. 1 Fluorine-substituted organic compounds are prevalent in materials chemistry and are increasingly utilized in approved pharmaceuticals and agrochemicals. 2 In the past decades, remarkable progress has been achieved in the synthesis of trifluoromethyl and difluoroalkyl compounds, which facilitated their commercial availability and synthetic accessibility. 3 In sharp contrast, the preparation of valuable monofluoroalkylated molecules remains a challenge that needs to be addressed. 4 The asymmetric construction of C−F-containing quaternary stereogenic centers through enantioselective reactions, including alkylation, arylation, Mannich, Michael addition, and allylation reactions, using versatile monofluorinated building blocks is particularly compelling. 5 In this scenario, the asymmetric cross-coupling reactions of α-fluoroalkyl halides with organozinc reagents, organoboron reagents, amino acids, and alkynes have been relatively well documented, 6 with most methods involving catalysis by transition metals, such as Pd, Ni, Ir, or Cu. In 2014, Fu developed the first catalytic asymmetric cross-coupling reactions of racemic α-halo-αfluoroketones with organozinc reagents to generate tertiary α-fluorinated acyclic ketones in the presence of a nickel/ bis(oxazoline) catalyst (Scheme 1a). 6b Prompted by Fu's

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Asymmetric Formal [5 + 2] Annulation of 3-Hydroxyquinolinones and Vinylethylene Carbonates through Pd/Cu Tandem Catalysis

Xiong,

Ge,

Zhou

et al. 2024

Org. Lett.

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The asymmetric [5 + 2] cycloaddition of VECs remains to be comparatively rare. Herein, we reported an enantioselective formal [5 + 2] annulation of 3-hydroxyquinolinones and vinylethylene carbonates (VECs) through Pd-and Cucatalyzed tandem allylation/asymmetric [1,3]-rearrangement/hemiketalization sequences. The strategy exhibits good substrate tolerance, affording a wide range of tricyclic quinolinones bearing two adjacent quaternary stereocenters in moderate to good yields with excellent enantioselectivities.

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Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers via Synergistic Pd/Cu Catalysis

Cited by 4 publications

References 58 publications

Pd‐Catalyzed Allylic Substitution Using Nucleophilic Amines: Access to Functionalized Mono‐ and Bis‐N‐Allyl Synthons

Pd‐Catalyzed Allylic Substitution Using Nucleophilic Amines: Access to Functionalized Mono‐ and Bis‐N‐Allyl Synthons

Copper-Catalyzed Asymmetric Tertiary Radical Cyanation for the Synthesis of Chiral Tetrasubstituted Monofluoroacyl Nitriles

Asymmetric Formal [5 + 2] Annulation of 3-Hydroxyquinolinones and Vinylethylene Carbonates through Pd/Cu Tandem Catalysis

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