Visible Light-Catalyzed Benzylic C–H Bond Chlorination by a Combination of Organic Dye (Acr⁺-Mes) and N-Chlorosuccinimide

Abstract

By combining “N-chlorosuccinimide (NCS)” as the safe chlorine source with “Acr+-Mes” as the photocatalyst, we successfully achieved benzylic C–H bond chlorination under visible light irradiation. Furthermore, benzylic chlorides could be converted to benzylic ethers smoothly in a one-pot manner by adding sodium methoxide. This mild and scalable chlorination method worked effectively for diverse toluene derivatives, especially for electron-deficient substrates. Careful mechanistic studies supported that NCS provided a hydrogen abstractor “N-centered succinimidyl radical,” which was responsible for the cleavage of the benzylic C–H bond, relying on the reducing ability of Acr•-Mes.

Site Selective Chlorination of C(sp3)−H Bonds Suitable for Late‐Stage Functionalization

“…[28] Benzylic C(sp 3 ) À H bonds also underwent chlorination with excellent site selectivity. A secondary benzylic C(sp 3 )ÀH bond in a series of functionalized 3-phenylpropanes containing a benzoate (15), bromide (16) and nitro group (17) were chlorinated in good to excellent yields. The tertiary benzylic C(sp 3 ) À H bond of a derivative of a precursor to the antiparasitic drug atovaquone [29] (18) also was successfully chlorinated, a functionalization that we found did not occur under published chlorination conditions [18,19] and, in general, is a poorly precedented transformation.…”

“…[13] Therefore, the development of methods capable of selectively incorporating a chlorine atom into biologically-active smallmolecules or natural products at a late stage could positively alter their efficacy and expedite the discovery of pharmaceuticals based on these scaffolds. [14] These potential benefits and the drawbacks of the classical C(sp 3 )ÀH bond chlorination methods have led to the development of alternative methods for the chlorination of C(sp 3 ) À H bonds, [15][16][17][18][19][20] but many of these methods rely on common reagents (such as N-chlorosuccinimide, TCCA, or tert-butyl hypochlorite) with the chlorine atom bound to an electronegative heteroatom. With these reagents, the XÀCl bond is sufficiently weak to undergo homolysis and initiate/ propagate the reaction, but, after such a step, generates a heteroatom-centered radical that is poorly chemo-selective and site-selective for H-atom abstraction.…”

“…As a consequence, multiple products form, and C(sp 3 ) À H bond chlorination reactions require a large excess of the substrate in which the CÀH bond reacts. The exceptions to this trend include chlorinations of benzylic C(sp 3 )ÀH bonds, which can be conducted often with high site selectivity because this bond is weaker than others, [16] and chlorination reactions that are directed intramolecularly to a particular site by a pre-installed functional group. [17] Three recent publications describe the chlorination of C(sp 3 )ÀH bonds with the substrate as the limiting reagent.…”

A Rational Approach to Organo‐Photocatalysis: Novel Designs and Structure‐Property Relationships

“…First introduced by Fukuzimi et al. in 2001, [12a] they are characterized by a high excited‐state oxidative power E * red =up to 2.32 V, E * ox =up to −0.57 V, [12b,c] and long lifetimes ( τ ) up to 31 ns [13] . Acridinium‐based PCs are soluble in numerous organic solvents, while showing high stability to electron‐rich species.…”

Copper(I)-catalysed site-selective C(sp3)–H bond chlorination of ketones, (E)-enones and alkylbenzenes by dichloramine-T

“…In the case of activated and benzylic C( sp 3 )–H bond chlorination, the majority are electrophilic or radical-based synthetic methods. The synthetic methods typically exploit chlorinating agents such as NCS ( N -chlorosuccinimide) and NaOCl under acidic, basic, high temperature, or UV irradiation reaction conditions to achieve moderate to excellent product site-selectivities 9 – 12 , 18 – 23 . For allylic or unactivated C( sp 3 )–H bond chlorination, the analogous site-selective reactions are even fewer and continue to pose a formidable synthetic challenge for a number of reasons 24 – 36 .…”