Metal-Catalyzed Benzylic Fluorination as a Synthetic Equivalent to 1,4-Conjugate Addition of Fluoride

Abstract

We explore in detail the iron-catalyzed benzylic fluorination of substrates containing aromatic rings and electron-withdrawing groups positioned β to one another, thus providing direct access to β-fluorinated adducts. This operationally convenient process can be thought of not only as a contribution to the timely problem of benzylic fluorination but also as a functional equivalent to a conjugate addition of fluoride, furnishing products in moderate to good yields and in excellent selectivity.

Site‐Selective Approach to β‐Fluorination: Photocatalyzed Ring Opening of Cyclopropanols

“…For example, the incorporation of a single fluorine atom at the β‐position has been shown to influence the conformational integrity of cyclic amines and amides,9 prevent mitochondrial β‐oxidation of fatty acids,10 and serve as an adequate positron emission tomography (PET) probe for elucidating a number of biosynthetic and metabolic pathways 11. Consequently, a number of methods have emerged pertaining to the targeted synthesis of β‐fluorinated carbonyl compounds 1c,f,g. 12, 13 It stands to reason that the development of an alternative, photocatalytic route to β‐fluorides from cyclopropanols would be highly desirable, providing a much needed tool in the armamentarium of the medicinal chemist.…”

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

“…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).…”

“…[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). 93,[104][105][106][107] Despite the difficulties associated with the activation of C-H bonds, which may require stronger reaction conditions i.e. more powerful oxidants or radical initiators, than those typically used for pre-activated substrates such as carboxylic acids, moderate TONs (up to 10) have been achieved via this route.…”

Transition Metal-Mediated and Metal-Catalyzed Carbon–Fluorine Bond Formation

“…29) Lectka applied substoichiometric amounts of an iron(II) complex to enable a simple and selective benzylic C-H bond fluorination protocol, with Selectfluor in acetonitrile at room temperature (Fig. 30) [58,59]. In 2014, Tang and coworkers reported a silver(I)-catalyzed difluorination of benzylic methylene groups (Fig.…”