Alkali‐Metal‐Alkoxide Powered Zincation of Fluoroarenes Employing Zinc Bis‐Amide Zn(TMP)₂

Abstract

Reminiscent of Lochmann-Schlosser superbase recipes, the addition of two molar equivalents of KOtBu to Zn(TMP) 2 (TMP = 2,2,6,6-tetramethylpiperidide) transforms this mild zinc bis-amide base to a powerful metalating agent able to perform facile regioselective zincation of a wide range of sensitive fluoroarenes. Structural authentication of the intermediates post ZnÀ H exchange demonstrates activation of both TMP groups to form a range of higher order bisaryl potassium zincates, isolable as solids and further functionalized in electrophilic interception reactions. Studies assessing the role of KOtBu reveal that the first equivalent undergoes co-complexation with Zn(TMP) 2 , enabling kinetic activation of the amide groups; whereas the second equivalent stabilizes the metalated intermediate preventing ligand redistribution. Showcasing its metalating power, this bimetallic KOtBu/Zn(TMP) 2 partnership, can effect zincation of toluene and benzene at room temperature.

Zinc-Mediated C–H Metalations in Modern Organic Synthesis

“…11,12 This review will focus on Csp 2 -H and Csp 3 -H functionalisation using zinc bases and showcase their broad application. We note that the use of (hetero)bimetallic zinc complexes for C-H zincation can give rise to exquisite selectivities and access to organozinc species otherwise out of reach; 19,20 many such examples report crystallographic characterisation of such organozincs or electrophilic trapping with I 2 only. We note that synergistic effects in organometallic chemistry have recently been reviewed, 21 and have herein focussed on examples used in total synthesis or C-C bond forming reactions.…”

“…18 Thus for most purposes, TMPZnCl•LiCl 3 remains the most convenient and widely applicable zinc base, and has come to be termed a 'turbo-zinc' reagent. 19 The discovery of mild organozinc compounds allowed for the functionalisation of moieties containing highly sensitive groups incompatible with traditional organolithium reagents such as ester, azide, nitro, and isothiocyanate groups without the need of incorporating extra synthetic steps to protect them. 6 It also ensured higher selectivity and alleviated the risk of unwanted nucleophilicity or ring fragmentation of heterocycles.…”

Applications of Transition Metal-Catalyzed ortho-Fluorine-Directed C–H Functionalization of (Poly)fluoroarenes in Organic Synthesis

“…As such, it complements our earlier review, which focused on the competition between C–F and C–H activation via interaction of fluorinated arenes with transition metal complexes. The ortho to fluorine functionalized reagents can be obtained, with selectivity being controlled by either electronic − or steric factors − that, in turn, reflect both thermodynamics and kinetics. We discuss their selectivity to undergo transition metal-catalyzed direct C–H arylation, heteroarylation, allylation, alkylation, alkynylation, olefination, carbonylation, amination, amidation, and hydroxylation processes, and relevant mechanistic studies.…”

One-Pot, Three-Component Assembly of Sulfides Using a Sulfoxide Reagent as a Sulfur Dication Equivalent

“…We demonstrate that a wide variety of Grignard reagents along with organolithium and organozinc reagents were viable substrates in our coupling platform, thus enabling diversity in substituents of sulfide products. With ever-increasing methods to prepare various organomagnesium and organozinc reagents, our method presented herein will find widespread use in the modular synthesis of sulfides for synthetic and medicinal applications.…”