Mono‐ and Difluorination of Benz­ylic Carbon Atoms

Koperniku, Ana; Liu, Hongqiang; Hurley, Paul B.

doi:10.1002/ejoc.201501329

Cited by 50 publications

(30 citation statements)

References 62 publications

(44 reference statements)

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“…In this context, the advantage of direct C-H fluorination over traditional fluorination methods is that it does not require the introduction of other functional groups. Although many methods have been developed for fluorination reactions [3,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46], including the addition of electrophilic fluorine to alkenes [1,28,32], the fluorination of aryl triflates [29] and arylpalladium complexes [2,47], few permit a one-step transformation of unactivated C(sp 3 )-H bonds to C(sp 3 )-F bonds [1,3,36,38,48]. Such a transformation would be highly valuable for the late-stage functionalization (LSF) of complex molecules, such as those in Scheme 1.…”

Section: Relevance Of Direct C-h Fluorination Methodsmentioning

confidence: 99%

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

Yakubov

Barham

2020

Beilstein J. Org. Chem.

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The importance of fluorinated products in pharmaceutical and medicinal chemistry has necessitated the development of synthetic fluorination methods, of which direct C–H fluorination is among the most powerful. Despite the challenges and limitations associated with the direct fluorination of unactivated C–H bonds, appreciable advancements in manipulating the selectivity and reactivity have been made, especially via transition metal catalysis and photochemistry. Where transition metal catalysis provides one strategy for C–H bond activation, transition-metal-free photochemical C–H fluorination can provide a complementary selectivity via a radical mechanism that proceeds under milder conditions than thermal radical activation methods. One exciting development in C–F bond formation is the use of small-molecule photosensitizers, allowing the reactions i) to proceed under mild conditions, ii) to be user-friendly, iii) to be cost-effective and iv) to be more amenable to scalability than typical photoredox-catalyzed methods. In this review, we highlight photosensitized C–H fluorination as a recent strategy for the direct and remote activation of C–H (especially C(sp3)–H) bonds. To guide the readers, we present the developing mechanistic understandings of these reactions and exemplify concepts to assist the future planning of reactions.

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Section: Relevance Of Direct C-h Fluorination Methodsmentioning

confidence: 99%

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

Yakubov

Barham

2020

Beilstein J. Org. Chem.

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“…This inconvenience has been overcome by introducing a fluorine atom onto the piperidine ring (130, Figure 18), reducing the basicity of the secondary amine by nearly two orders of magnitude, resulting in a marked betterment The beneficial properties of benzyl fluorides in lead optimization 102,103 have motivated an intense research activity in late stage fluorination of benzylic positions. 101 Britton and colleagues 104 have reported a late-stage fluorination of benzylic positions employing NFSI using either a decatungstate photocatalyst or AIBN-initiation.…”

Section: -Methods For Fluorination Of Sugars and Nucleobase Derivatmentioning

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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“…However, only in recent years has benzylic fluorination started to gain increased attention, proving to be a powerful tool for site-specific C(sp 3 )-F bond formation. 93,[104][105][106][107][108][109][110][111][112][113][114] Generally, amongst these studies, different fluorination routes can be identified: (i) electrophilic fluorination employing Selectfluor®, N-fluoropiridinium salts and NFSI as fluorinating sources, 93,[104][105][106][107] (ii) nucleophilic fluorination with triethylamine trihydrofluoride, TREAT•HF, and fluor-ide salts, 108,109 and (iii) thermal-or photocatalysed radical fluorination. [110][111][112][113] Amongst these, benzylic fluorination catalysed by transition metal complexes using electrophilic fluorinating reagents represents the most exploited (see examples in Scheme 10, entries 1-3).…”

Section: Benzylic Fluorinationmentioning

confidence: 99%

Catalytic C(sp³)–F bond formation: recent achievements and pertaining challenges

Tarantino

Hammond

2020

Green Chem.

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Mono‐ and Difluorination of Benzylic Carbon Atoms

Cited by 50 publications

References 62 publications

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

Fluorination methods in drug discovery

Catalytic C(sp³)–F bond formation: recent achievements and pertaining challenges

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Mono‐ and Difluorination of Benz­ylic Carbon Atoms

Cited by 50 publications

References 62 publications

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

Fluorination methods in drug discovery

Catalytic C(sp3)–F bond formation: recent achievements and pertaining challenges

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Product

Resources

About

Mono‐ and Difluorination of Benzylic Carbon Atoms

Catalytic C(sp³)–F bond formation: recent achievements and pertaining challenges