Asymmetric benzylic C(sp3)−H acylation via dual nickel and photoredox catalysis

Abstract

Asymmetric C(sp3)−H functionalization is a persistent challenge in organic synthesis. Here, we report an asymmetric benzylic C−H acylation of alkylarenes employing carboxylic acids as acyl surrogates for the synthesis of α-aryl ketones via nickel and photoredox dual catalysis. This mild yet straightforward protocol transforms a diverse array of feedstock carboxylic acids and simple alkyl benzenes into highly valuable α-aryl ketones with high enantioselectivities. The utility of this method is showcased in the gram-scale synthesis and late-stage modification of medicinally relevant molecules. Mechanistic studies suggest a photocatalytically generated bromine radical can perform benzylic C−H cleavage to activate alkylarenes as nucleophilic coupling partners which can then engage in a nickel-catalyzed asymmetric acyl cross-coupling reaction. This bromine-radical-mediated C−H activation strategy can be also applied to the enantioselective coupling of alkylarenes with chloroformate for the synthesis of chiral α-aryl esters.

Stereodivergent Synthesis of BothZ- andE-Alkenes by Photoinduced, Ni-Catalyzed Enantioselective C(sp3)–H Alkenylation

“…On the basis of these mechanistic observations and our recent studies, a plausible mechanism is proposed in Figure . The radical alkenylation is initiated by oxidative addition of a vinyl bromide to Ni(0) catalyst I to furnish Ni­(II) species II .…”

“…Elegant studies from Yoon and Meyer on the counteranion effects of photocatalysts have demonstrated that a more coordinating counteranion can lead to a decrease in lifetime or triplet excited-state energy, which might account for such a tunable stereoselectivity achieved by a judicious choice of counteranions . Two chiral nickel catalysts employed in our recent studies on the C­(sp 3 )–H acylation led to low efficiency for this newly developed alkenylation reaction (entries 9 and 10). , Finally, the control experiments revealed that nickel catalyst, photocatalyst, and light are essential for the alkenylation product formation (entry 11).…”

“…(A) Examples of importance as versatile intermediates in the preparation of medicinal agents. (B) Ni/Photoredox dual-catalyzed enantioselective C­(sp 3 )–H functionalization (refs , , and ). (C) This study.…”

“…While significant advances have been achieved for the nickel and photoredox catalyzed nonasymmetric C­(sp 3 )–H functionalization reactions, the development of enantioselective variants remains a great challenge . Nevertheless, early studies by Lu, Martin, and our group have demonstrated that direct C­(sp 3 )–H functionalization reactions enabled by dual nickel photoredox catalysis can be rendered enantioselective. , However, few successful examples are typically limited to the use of aryl halides as electrophiles, and large excesses of C–H coupling partners are required to achieve effective C–H arylation.…”

“…To address these challenges, our laboratory has recently achieved the direct enantioselective C­(sp 3 )–H acylation of α-amino and benzylic C­(sp 3 )–H bonds with in situ-activated carboxylic acids via bromine-radical-mediated C–H activation . Encouraged by this initial progress and in an effort to expand the electrophile scope of enantioselective radical C­(sp 3 )–H functionalization, we questioned if it might be possible to couple the benzylic C–H bonds with readily available vinyl halides to address the aforementioned challenges for the asymmetric synthesis of stereodefined functionalized alkenes (Figure C).…”