Transition-Metal-Free Oxyfluorination of Olefinic Amides for the Synthesis of Fluorinated Heterocycles

Zhao, Jiyang; Duan, Xin‐Hua; Ye, Hua; Guo, Li‐Na

doi:10.1021/acs.joc.5b01909

Cited by 53 publications

(51 citation statements)

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“…[5] They can also serve as versatile building blocks and precursors for formation of reactive intermediates. [10] Despite these advances, to our knowledge, there is no report on the practical, general, and catalytic synthesis of fluoroalkylated iminoisobenzofurans. [6] Representative synthetic methods toward these compounds include Pd-catalyzed three-component coupling of in situ-formed arynes, [7] Pd-catalyzed cyclization/coupling of o-alkynylbenzamides, [8] Ag-and Au-catalyzed cycloisomerization of o-alkynylbenzohydroxamic acid derivatives, [9] as well as transition metal-free oxyfluorination and thiocyanooxygenation of olefinic amides.…”

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confidence: 99%

Visible Light Photocatalytic Radical Addition/Cyclization Reaction of o‐Vinyl‐N‐Alkoxybenzamides for Synthesis of CF₃‐Containing Iminoisobenzofurans

et al. 2018

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confidence: 99%

Visible Light Photocatalytic Radical Addition/Cyclization Reaction of o‐Vinyl‐N‐Alkoxybenzamides for Synthesis of CF₃‐Containing Iminoisobenzofurans

et al. 2018

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“…Interestingly,t he change of the electrophilicf luorine source from 1 to the fluoro aza compound selectfluor (11)w as accompanied with ac ompletely altered chemoselectivity.N ow the oxazine 10 a was formed solely in 61 %y ield after 24 h( entry 10). [20,21] This result impressively shows that the fluoro iodine(III) reagent 1 is not only significantly more reactive but also provides ac ompletely different chemoselectivity when compared to the common electrophiles such as 11.W ith the application of 1,n ovel paths in electrophilic fluorinations are now available, leading to unprecedented fluorinated scaffolds.…”

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confidence: 99%

A Fluorination/Aryl Migration/Cyclization Cascade for the Metal‐Free Synthesis of Fluoro‐Benzoxazepines

Ulmer

Brunner

Arnold

et al. 2015

Chemistry A European J

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Fluorinated organic molecules are of high interest for many applications across chemical and medical disciplines. Efficient methods for the synthesis of such compounds are thus needed. Within this work, application of the bench-stable cyclic hypervalent iodine(III) fluoro reagent 1 facilitated the development of an efficient, metal-free method for the preparation of the novel class of 4-fluoro-1,3-benzoxazepines starting from readily available styrenes. The efficacy and broad applicability of this concept is demonstrated by the synthesis of 20 structurally diverse congeners in high yields, regio-, and diastereoselectivities. The presented method provides complementary chemoselectivity when compared to the common, commercially available electrophilic fluorination reagents, such as selectfluor. First mechanistic investigations with isotopically labeled substrates reveal a complex reaction mechanism, proceeding via an unusual fluorination/1,2-aryl migration/cyclization cascade.

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“…Benzoxazines are present in bioactive compounds, such as the anxiolytic and anticonvulsant drug etifoxine 100 74,73 , or progesterone receptor agonists 101 ( Figure 13). Triazoles substituted with methylpyridine, n-heptyl, methylnaphthalene at the 1-position (and a phenyl group at the 4-position) also afford good yields of 5-fluorotriazole derivatives (products 124-126).…”

Section: -Synthesis Of Benzoxazine Coresmentioning

confidence: 99%

Fluorination methods in drug discovery

2016

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Fluorination reactions of medicinal and biologically-active compounds will be discussed. Late stage fluorination strategies of medicinal targets have recently attracted considerable attention on account of the influence that the fluorine atom can impart to targets of medicinal importance, such as a modulation of lipophilicity, electronegativity, basicity and bioavailability, this latter as a consequence of membrane permeability. Therefore, the recourse to late-stage fluorine substitution on compounds with already known and relevant biological activity can provide the pharmaceutical industry with new leads with improved medicinal properties. The fluorination strategies will take into account different fluorinating reagents, nucleophilic, electrophilic and of radical nature. Diverse families of organic compounds such as (hetero)aromatic rings, and aliphatic substrates (sp 3 , sp 2 , and sp carbon atoms) will be studied in late-stage fluorination reaction strategies. The omniphobicity/lipophilicity and electrostatic interactions can be considered among the most prominent effects. Thus, introducing fluorine into an organic compound can significantly alter its biological properties.One other subtle but important effect of introducing fluorine into the backbone of a medicinal target is the inflection of acidity and basicity of the parent compound 4 , which can change, inter alia, the binding affinity, and bioavailability. Highly basic groups can have a detrimental effect on the bioavailability of a drug. Thus introducing a fluorine atom next to a basic group can reduce its basicity, enhancing its membrane permeability, and increasing bioavailability. Although the replacement of hydrogen for fluorine does not have a profound steric influence, electrostatic interactions with other groups can change conformations significantly. The replacement of hydrogen for fluorine on aromatic rings is a well-known strategy to decelerate oxidative metabolic processes by Cytochrome P450 monooxygenases. In this respect, the electron-withdrawing properties of fluorine on aromatic rings, which can slow down hydrolytic metabolism, alter reaction rates and stability of intermediates. Fluorine substitution on aromatic rings is also known to increase binding affinity, as a result of enhancing electrostatic interactions.However, it is difficult to predict the influence of fluorine substitution on the overall profile in a given situation.As numerous reports attest 1 , the number of marketed drugs that contain a fluorine atom has increased rapidly. As of 2009, the FDA-had approved >140 fluorine-containing drugs. This review article is intended to present new synthetic methodologies 9 for accomplishing fluorination reactions on molecules (drugs/prodrugs) with pharmacological activity. It is not our aim (Figure 3). would be beneficial to the syntheses. 3a.-Conversion of C Ar -H into C Ar -F BondsXu and co-workers 38 have developed an ortho C-H bond fluorination of 2-phenoxyl pyridine derivatives through a palladium-catalyzed reaction v...

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Transition-Metal-Free Oxyfluorination of Olefinic Amides for the Synthesis of Fluorinated Heterocycles

Abstract: A series of fluorinated 4H-3,1-benzoxazines and iminoisobenzofurans have been synthesized through the electrophilic fluorocyclization of olefinic amides. This methodology is highlighted by its mild conditions, wide substrate scope, and good functional group tolerance.

Cited by 53 publications

References 56 publications

Visible Light Photocatalytic Radical Addition/Cyclization Reaction of o‐Vinyl‐N‐Alkoxybenzamides for Synthesis of CF₃‐Containing Iminoisobenzofurans

Visible Light Photocatalytic Radical Addition/Cyclization Reaction of o‐Vinyl‐N‐Alkoxybenzamides for Synthesis of CF₃‐Containing Iminoisobenzofurans

A Fluorination/Aryl Migration/Cyclization Cascade for the Metal‐Free Synthesis of Fluoro‐Benzoxazepines

Fluorination methods in drug discovery

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Transition-Metal-Free Oxyfluorination of Olefinic Amides for the Synthesis of Fluorinated Heterocycles

Abstract: A series of fluorinated 4H-3,1-benzoxazines and iminoisobenzofurans have been synthesized through the electrophilic fluorocyclization of olefinic amides. This methodology is highlighted by its mild conditions, wide substrate scope, and good functional group tolerance.

Cited by 53 publications

References 56 publications

Visible Light Photocatalytic Radical Addition/Cyclization Reaction of o‐Vinyl‐N‐Alkoxybenzamides for Synthesis of CF3‐Containing Iminoisobenzofurans

Visible Light Photocatalytic Radical Addition/Cyclization Reaction of o‐Vinyl‐N‐Alkoxybenzamides for Synthesis of CF3‐Containing Iminoisobenzofurans

A Fluorination/Aryl Migration/Cyclization Cascade for the Metal‐Free Synthesis of Fluoro‐Benzoxazepines

Fluorination methods in drug discovery

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Visible Light Photocatalytic Radical Addition/Cyclization Reaction of o‐Vinyl‐N‐Alkoxybenzamides for Synthesis of CF₃‐Containing Iminoisobenzofurans

Visible Light Photocatalytic Radical Addition/Cyclization Reaction of o‐Vinyl‐N‐Alkoxybenzamides for Synthesis of CF₃‐Containing Iminoisobenzofurans